Phenyl thiophene carboxamide compounds as inhibitors of the enzyme IKK-2

ABSTRACT

The invention relates to thiophene carboxamides of formula (I), wherein A, R 1 , R 2 , R 3 , n and X are as defined in the specification, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application and claims priority to U.S.application Ser. No. 10/484,569, filed on Jan. 22, 2004 now U.S. Pat.No. 7,125,896 which claims priority under 35 USC §371 to internationalapplication number PCT/SE02/01403, filed Jul. 19, 2002, which claimspriority to Swedish patent application number 0102616-0, filed Jul. 25,2001.

FIELD OF THE INVENTION

The present invention relates to thiophene carboxamide derivatives,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

The NF-κB (nuclear factor κB) family is composed of homo- andheterodimers of the Rel family of transcription factors. A key role ofthese transcription factors is to induce and coordinate the expressionof a broad spectrum of pro-inflammatory genes including cytokines,chemokines, interferons, MHC proteins, growth factors and cell adhesionmolecules (for reviews see Verma et. al., Genes Dev. 9:2723-35, 1995;Siebenlist et. al., Ann. Rev. Cell. Biol. 10:405-455, 1994; Bauerle andHenkel, Ann. Rev. Immunol., 12:141-179, 1994; Barnes and Karin, NewEngl. J. Med., 336:1066-1071, 1997).

The most commonly found Rel family dimer complex is composed of p50 NFkBand p65 RelA (Baeuerle and Baltimore, Cell 53:211-217, 1988; Baeuerleand Baltimore, Genes Dev. 3:1689-1698, 1989). Under resting conditionsNF-κB dimers are retained in the cytoplasm by a member of the IκB familyof inhibitory proteins (Beg et. al., Genes Dev., 7:2064-2070, 1993;Gilmore and Morin, Trends Genet. 9:427-433, 1993; Haskil et. al., Cell65:1281-1289, 1991). However, upon cell activation by a variety ofcytokines or other external stimuli, IκB proteins become phosphorylatedon two critical serine residues (Traenckner et. al., EMBO J., 14:2876,1995) and are then targeted for ubiquitination and proteosome-mediateddegradation (Chen, Z. J. et. al., Genes and Dev. 9:1586-1597, 1995;Scherer, D. C. et. al., Proc. Natl. Acad. Sci. USA 92:11259-11263, 1996;Alkalay, I. et. al., Proc. Natl. Acad. Sci. USA 92:10599-10603, 1995).The released NF-κB is then able to translocate to the nucleus andactivate gene transcription (Beg et. al., Genes Dev., 6:1899-1913,1992).

A wide range of external stimuli have been shown to be capable ofactivating NF-κB (Baeuerle, P. A., and Baichwal, V. R., Adv. Immunol.,65:111-136, 1997). Although the majority of NF-κB activators result inIκB phosphorylation, it is clear that multiple pathways lead to this keyevent. Receptor-mediated NF-κB activation relies upon specificinteractions between the receptor and adapter/signalling molecules (forexample, TRADD, RIP, TRAF, MyD88) and associated kinases (IRAK, NIK)(Song et. al., Proc. Natl. Acad. Sci. USA 94:9792-9796, 1997; Natoli et.al., JBC 272:26079-26082, 1997). Environmental stresses such as UV lightand γ-radiation appear to stimulate NF-κB via alternative, less defined,mechanisms.

Recent publications have partially elucidated the NF-κB activation. Thiswork has identified three key enzymes which regulate specific IκB/NF-κBinteractions: NF-κB inducing kinase (NIK) (Boldin et. al., Cell85:803-815, 1996), IκB kinase-1 (IKK-1) (Didonato et. al., Nature388:548, 1997; Regnier at. al., Cell 90:373 1997) and IκB kinase-2(IKK-2) (Woronicz et. al., Science 278:866, 1997; Zandi et. al., Cell91:243, 1997).

NIK appears to represent a common mediator of NF-κB signalling cascadestriggered by tumour necrosis factor and interleukin-1, and is a potentinducer of IκB phosphorylation. However NIK is unable to phosphorylateIκB directly.

IKK-1 and IKK-2 are thought to lie immediately downstream of NIK and arecapable of directly phosphorylating all three IκB sub-types. IKK-1 andIKK-2 are 52% identical at the amino acid level but appear to havesimilar substrate specificities; however, enzyme activities appear to bedifferent: IKK-2 is several-fold more potent than IKK-1. Expressiondata, coupled with mutagenesis studies, suggest that IKK-1 and IKK-2 arecapable of forming homo- and heterodimers through their C-terminalleucine zipper motifs, with the heterodimeric form being preferred(Mercurio et. al., Mol. Cell Biol., 19:1526, 1999; Zandi et. al.,Science; 281:1360, 1998; Lee et. al., Proc. Natl. Acad. Sci. USA95:9319, 1998).

NIK, IKK-1 and IKK-2 are all serine/threonine kinases. Recent data hasshown that tyrosine kinases also play a role in regulating theactivation of NF-κB. A number of groups have shown that TNF-α inducedNF-κB activation can be regulated by protein tyrosine phosphatases(PTPs) and tyrosine kinases (Amer et. al., JBC 273:29417-29423, 1998; Huet. al., JBC 273:33561-33565, 1998; Kaekawa et. al., Biochem. J.337:179-184, 1999; Singh et. al., JBC 271 31049-31054, 1996). Themechanism of action of these enzymes appears to be in regulating thephosphorylation status of IκB. For example, PTP1B and an unidentifiedtyrosine kinase appear to directly control the phosphorylation of alysine residue (K42) on IκB-α, which in turn has a critical influence onthe accessibility of the adjacent serine residues as targets forphosphorylation by IKK.

Several groups have shown that IKK-1 and IKK-2 form part of a‘signalosome’ structure in association with additional proteinsincluding IKAP (Cohen et. al., Nature 395:292-296, 1998; Rothwarf et.al., Nature 395:297-300, 1998), MEKK-1, putative MAP kinase phosphatase(Lee et. al., Proc. Natl. Acad. Sci. USA 95:9319-9324, 1998), as well asNIK and IκB. Data is now emerging to suggest that although both IKK-1and IKK-2 associate is with NIK, they are differentially activated, andtherefore might represent an important integration point for thespectrum of signals that activate NF-κB. Importantly, MEKK-1 (one of thecomponents of the putative signalosome and a target for UV light, LPSinduced signalling molecules and small GTPases) has been found toactivate IKK-2 but not IKK-1 Similarly, NIK phosphorylation of IKK-1results in a dramatic increase in IKK-1 activity but only a small effecton IKK-2 (for review, see Mercurio, F., and Manning, A. M., CurrentOpinion in Cell Biology, 11:226-232, 1999).

Inhibition of NF-κB activation is likely to be of broad utility in thetreatment of inflammatory disease.

There is accumulating evidence that NF-κB signalling plays a significantrole in the development of cancer and metastasis. Abnormal expression ofc-Rel, NF-κB2 or IκBα have been described in a number of tumour typesand tumour cell lines, and there is now data to show that constitutiveNF-κB signalling via IKK-2 takes place in a wide range of tumour celllines. This activity has been linked to various upstream defects ingrowth factor signalling such as the establishment of autocrine loops,or the presence of oncogene products e.g. Ras, AKT, Her2, which areinvolved in the activation of the IKK complex. Constitutive NF-κBactivity is believed to contribute to oncogenesis through activation ofa range of anti-apoptotic genes e.g. Al/Bfi-1, IEX-1, XIAP, leading tothe suppression of cell death pathways, and transcriptional upregulationof cyclin D1 which promotes cell growth. Other data indicate that thispathway is also likely to be involved in the regulation of cell adhesionand cell surface proteases. This suggests a possible additional role forNF-κB activity in the development of metastasis. Evidence confirming theinvolvement of NF-κB activity in oncogenesis includes the inhibition oftumour cell growth in vitro and in vivo on expression of a modified formof IκBα (super-repressor IκBα).

In addition to the constitutive NF-κB signalling observed in many tumourtypes, it has been reported that NF-κB is also activated in response tocertain types of chemotherapy. Inhibition of NF-κB activation throughexpression of the super-repressor form of IκBα in parallel withchemotherapy treatment has been shown to enhance the antitumour effectof the chemotherapy in xenograft models. NF-κB activity is thereforealso implicated in inducible chemoresistance.

DISCLOSURE OF THE INVENTION

According to the present invention, there is provided a compound offormula (I)

in which:

R¹ represents NH₂ or R¹ represents a methyl group optionally substitutedby one or more groups selected independently from C₁-C₄ alkyl, C₃-C₆cycloalkyl, halogen, hydroxyl, C₁-C₄ alkoxy, S(O)_(v)CH₃ and NR⁴R⁵;

X represents O or S;

R² represents hydrogen, halogen, cyano, nitro, —NR⁶R⁷, —CONR⁶R⁷, —COOR⁶,—NR⁶COR⁷, —S(O)_(m)R⁶, —SO₂NR⁶R⁷, —NR⁶SO₂R⁷, C₁-C₂ alkyl,trifluoromethyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, trifluoromethoxy, C₁-C₂alkoxy or C₁-C₂ alkanoyl;

A represents a phenyl ring or a 5- to 7-membered heteroaromatic ringcontaining one to three heteroatoms selected independently from O, N andS; said phenyl or heteroaromatic ring being optionally substituted byone or more substituents selected independently from halogen, cyano,nitro, —NR⁸R⁹, —CONR⁸R⁹, —COOR⁸, —NR⁸COR⁹, —S(O)_(s)R⁸, —SO₂NR⁸R⁹,—NR⁸SO₂R⁹, C₁-C₆ alkyl, trifluoromethyl, —(CH₂)_(t)R¹⁰, —(CH₂)_(t)R¹¹ or—OR¹²;

n represents an integer 1 or 2; and when n represents 2, each R³ groupmay be selected independently;

R³ represents a group —W—Y—Z wherein:

W represents O, S(O)_(r), NR¹³, —CH₂, —CH₂—O— or a bond;

Y represents a bond or a group —(CH₂)_(p)-T-(CH₂)_(q)— wherein p and qindependently represent an integer 0, 1 or 2; and T represents O, —CO—or CR¹⁴R¹⁵;

R¹⁴ and R¹⁵ independently represent H, CH₃ or F;

or R¹⁴ represents H or CH₃ and R¹⁵ represents hydroxyl or OCH₃;

or the group CR¹⁴R¹⁵ together represents a C₃-C₆ cycloalkyl ring;

Z represents:

(a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containingone to three heteroatoms selected independently from O, N and S; saidphenyl or heteroaromatic ring being optionally substituted by one ormore substituents selected independently from halogen, cyano, —NR¹⁶R¹⁷,—CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶—NR¹⁶COR¹⁷, —S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷,—NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl andC₁-C₆ alkoxy; said alkyl or alkoxy group being optionally furthersubstituted by one or more groups selected from halogen, cyano,hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; or

-   -   (b) a 3- to 8-membered saturated or partially unsaturated        monocyclic or saturated bicyclic ring system optionally        incorporating one or two heteroatoms selected independently from        O, N and S, and optionally incorporating a carbonyl group; said        ring system being optionally substituted by one or more        substituents selected independently from halogen, cyano,        —NR¹⁶R¹⁷, —CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶, —NR¹⁶COR¹⁷, —S(O)_(u)R¹⁶,        —SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ alkyl, C₃-C₆ cycloalkyl and C₁-C₆ alkoxy; said        alkyl or alkoxy group being optionally further substituted by        one or more groups selected from halogen, cyano, hydroxyl, C₃-C₆        cycloalkyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; provided that said        saturated monocyclic ring Z is not bonded to Y through nitrogen        if the group —W—Y— represents —(CH₂)₂₋₄— or —O—(CH₂)₂₋₄— when        the saturated ring Z is also unsubstituted; or

(c) if W represents O, then Z may also represent hydroxyl, OCH₃, CF₃,CHF₂ or CH₂F, provided that the group —Y—Z does not thereby represent—O—(CH₂)₂₋₄—OCH₃;

R¹⁰ and R¹¹ independently represent NR²⁰R²¹ where R²⁰ and R²¹ areindependently hydrogen or C₁-C₆ alkyl optionally substituted by C₁-C₄alkoxy; or the group NR²⁰R²¹ represents a 5- or 6-membered saturatedazacyclic ring optionally containing a further O, S or NR²² group; whereR²² is hydrogen or C₁-C₆ alkyl; or R¹⁰ and R¹¹ independently representC₁-C₆ alkoxy;

R⁴ and R⁵ independently represent H or C₁-C₄ alkyl; or the group NR⁴R⁵represents a 5- or 6-membered saturated azacyclic ring optionallycontaining a further O, S or NR²³ group; where R²³ is hydrogen or C₁-C₄alkyl;

R⁶ and R⁷ independently represent H or C₁-C₂ alkyl;

R⁸, R⁹ and R¹² independently represent H or C₁-C₆ alkyl;

R¹³ represents H or C₁-C₄ alkyl;

R¹⁶ and R¹⁷ independently represent H or C₁-C₆ alkyl optionallysubstituted by OH, C₁-C₄ alkoxy or one or more fluoro atoms; or thegroup NR¹⁶R¹⁷ represents a 5- or 6-membered saturated azacyclic ringoptionally containing a further O, S or NR²⁴ group; where R²⁴ ishydrogen or C₁-C₆ alkyl optionally substituted by OH, C₁-C₄ alkoxy orone or more fluoro atoms;

R¹⁸ and R¹⁹ independently represent H or C₁-C₄ alkyl; or the groupNR¹⁸R¹⁹ represents a 5- or 6-membered saturated azacyclic ringoptionally containing a further O, S or NR²⁵ group; where R²⁵ ishydrogen or C₁-C₄ alkyl;

m, r, s, u and v independently represent an integer 0, 1 or 2;

t represents an integer 2, 3 or 4;

and pharmaceutically acceptable salts thereof:

with the proviso that the following two compounds are excluded:

-   2-[(aminocarbonyl)amino]-5-(4-[2-(1-(2,2,6,6-tetramethyl)piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-(thiazol-4-yl-methoxy)phenyl)-3-thiophenecarboxamide.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

In one embodiment, the invention provides compounds of formula (I)wherein Z represents:

(a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containingone to three heteroatoms selected independently from O, N and S; saidphenyl or heteroaromatic ring being optionally substituted by one ormore substituents selected independently from halogen, cyano, —NR¹⁶R¹⁷,—CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶, —NR¹⁶COR¹⁷, —S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷,—NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl andC₁-C₆ alkoxy; said alkyl or alkoxy group being optionally furthersubstituted by one or more groups selected from halogen, cyano,hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; or

(b) a saturated 3- to 7-membered ring optionally incorporating one ortwo heteroatoms selected independently from O, N and S, and optionallyincorporating a carbonyl group; said saturated ring being optionallysubstituted by one or more substituents selected independently fromhalogen, cyano, —NR¹⁶R¹⁷, CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶, —NR¹⁶COR¹⁷,—S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group beingoptionally further substituted by one or more groups selected fromhalogen, cyano, hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; provided that saidsaturated ring Z is not bonded to Y through nitrogen if the group —W—Y—represents —(CH₂)₂₋₄— or —O—(CH₂)₂₋₄— when the saturated ring Z is alsounsubstituted; or

(c) if W represents O, then Z may also represent hydroxyl, OCH₃, CF₃,CHF₂ or CH₂F, provided that the group —Y—Z does not thereby represent—O—(CH₂)₂₋₄—OCH₃; and all other substituents are as defined above.

In one embodiment, X in formula (I) represents oxygen.

In another embodiment, R¹ in formula (I) represents NH₂.

Suitably the group A in formula (I) is a phenyl group or a 5- to7-membered heteroaromatic ring containing one to three heteroatomsselected independently from O, N and S; said phenyl or heteroaromaticring being optionally substituted by one- or more substituents selectedindependently from halogen, cyano, nitro, —NR⁸R⁹, —CONR⁸R⁹, —COOR⁸,—NR⁸COR⁹, —S(O)_(s)R⁸, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹, C₁-C₆ alkyl,trifluoromethyl, —(CH₂)_(t)R¹⁰, —(CH₂)_(t)R¹¹ or —O¹². In oneembodiment, A represents optionally substituted phenyl. In anotherembodiment, A represents an optionally substituted pyridyl.

In one embodiment, the group R² in formula (I) represents H, halogen orC₁-C₂ alkyl. In another embodiment, the group R² represents H or methyl.In another embodiment, the group R² in formula (I) represents H.

In another embodiment, W in formula (I) represents O, CH₂ or a bond.

In another embodiment, Y in formula (I) represents —CH₂—CH₂— or a bond.

In another embodiment, Z in formula (I) represents a 3- to 8-memberedsaturated or partially unsaturated monocyclic or saturated bicyclic ringsystem optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said ring system being optionally substituted by one or moresubstituents selected independently from halogen, cyano, —NR¹⁶R¹⁷,—CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶, —N¹⁶COR¹⁷, —S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷,—NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl, C₃-C₆cycloalkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group being optionallyfurther substituted by one or more groups selected from halogen, cyano,hydroxyl, C₃-C₆ cycloalkyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; provided that saidsaturated monocyclic ring Z is not bonded to Y through nitrogen if thegroup —W—Y— represents —(CH₂)₂₋₄— or —O—(CH₂)₂₋₄— when the saturatedring Z is also unsubstituted.

In another embodiment, Z in formula (I) represents a phenyl ring or a 5-or 6-membered heteroaromatic ring containing one to three heteroatomsselected independently from O, N and S; said phenyl or heteroaromaticring being optionally substituted by one or more substituents selectedindependently from halogen, cyano, —NR¹⁶R¹⁷, —CONR¹⁶R¹⁷, —COOR¹⁶,—COR¹⁶—NR¹⁶COR¹⁷, —S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁷, hydroxyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl and C₁-C₆ alkoxy; said alkylor alkoxy group being optionally further substituted by one or moregroups selected from halogen, cyano, hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹.

In one embodiment, n has the value 1.

The compounds of formula (I) and their pharmaceutically acceptable saltshave the advantage that they are inhibitors of the enzyme IKK-2.

The invention further provides a process for the preparation ofcompounds of formula (I) or a pharmaceutically acceptable salt,enantiomer or racemate thereof.

According to the invention there is also provided a compound of formula(I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

Another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofdiseases or conditions in which inhibition of IKK-2 activity isbeneficial.

A more particular aspect of the invention provides the use of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofinflammatory disease.

According to the invention, there is also provided a method of treating,or reducing the risk of, diseases or conditions in which inhibition ofIKK-2 activity is beneficial which comprises administering to a personsuffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt mate thereof.

More particularly, there is also provided a method of treating, orreducing the risk of, inflammatory disease in a person suffering from orat risk of, said disease, wherein the method comprises administering tothe person a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

Particular compounds of the invention include those exemplified herein:

-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-biphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(3,5-dimethylisoxazolyl)methoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(4-chlorophenyl)methoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(5-chlorothien-2-yl)methoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-{4-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(thiazol-4-yl)methoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(1,2,5-thiadiazol-3-yl)methoxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-(4-[(1-methylperhydroazepin-3-yl)oxy]phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(pyrrolidin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(2,2-difluoroethoxy)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(piperidin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(cyclopentyloxypyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(4-ethanesulfonylpiperazin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-[(tetrahydrofuran-2-yl)methoxy]pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(furan-2-ylmethoxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(4-acetyl)piperazin-1-yl]-pyridine}-3-thiophenecarboxamide;-   (R)-2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(1-isopropyl-pyrrolidin-3-yloxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(1-t-butyloxycarbonyl-piperidin-4-yloxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(piperidin-4-yloxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(1-(2-methoxyethyl)-piperidin-4-yloxy)]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(N-methanesulphonyl)-piperidin-4-yloxy]-pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(4,4-difluoropiperidin-1-yl)pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(pyrrolidin-1-yl)-5-methyl]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(thien-2-ylmethoxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(cyclopentylmethoxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[3-(6-benzyloxy)pyridine]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-ylmethoxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(cyclopropylmethoxy)]pyridine}-3-thiophenecarboxamide;-   (S)-2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydropyran-4-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(tetrahydrothiopyran-3-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(1-isopropylazetidin-3-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(benzyloxy-2-ethoxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(N-methylpiperidin-3-yloxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(2-(1-pyrrolidin-2-one)ethoxy)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[3-(6-(morpholin-4-yl))pyridine]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[6-(4-methylpiperazin-1-yl)]pyridine}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-[1,3,4-oxadiazol-2-yl]-2-phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(4-cyclopropylmethoxyphenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[3-(1,3-thiazol-4-ylmethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-(N-morpholinyl)]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-(N-piperdinyl)]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-(N-pyrrolidinyl)]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-{4-(t-butyloxycarbonyl)piperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(-5-[2-{4H-piperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-{4-methylpiperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-(3-dimethylaminopyrrolidin-1-yl)]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-{2(S)-aminocarbonylpyrrolidin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-[2-{4-acetylpiperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-{2-[4,4-difluoropiperidin-1-yl]}pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(5-{2-[3,3-difluoropyrrolidin-1-yl]}pyrimidinyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-(5-N-morpholinomethyl)thienyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-benzyloxyphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-(4-fluorophenylmethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-(2-[4-fluorophenyl]ethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-(2-[4-chlorophenyl]ethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-(2-phenylethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4-chlorophenylmethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[2-(N-morpholinyl)]ethylthio)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[2-(N-pyrrolidinyl)]ethylthio)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[2-(N-piperidinyl)]ethylthio)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(pyrrolidinyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(piperidinyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(N-imidazolyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-{(1-methylpyrrolidin-2-on-4-yl)methoxy}pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(2-methoxyethoxy)ethoxy]-phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(cyclopropylmethoxy)ethoxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[6-(2,2-dimethyl-3-pyrrolidinylpropoxy)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-chloro-4-(tetrahydrofuran-2-ylmethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{-(tetrahydrofuran-2-ylmethoxy)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[(6-cyclopropylmethylthio)pyridin-3-yl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(2-methoxyethoxy)ethoxy]-3-methylphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3-chloro-4-[2-(2-methoxyethoxy)ethoxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(4-methylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(4-isopropylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(pyrrolidinylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide;-   3-[(aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide;-   3-[(aminocarbonyl)amino]-5-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[(6-{4-morpholino}methyl)pyridin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[3-(morpholin-4-ylmethyl)-4-isobutoxyphenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[3-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-{[2-(methoxymethyl)morpholin-4-yl]methyl}phenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[3-fluoro-4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(1-{piperidin-1-yl}ethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[(1R)-1-morpholin-4-ylethyl]phenyl}thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}phenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(piperidin-1-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]phenyl}thiophene-3-carboxamide;-   5-{4-[(4-acetylpiperazin-1-yl)methyl]phenyl}-2-[(aminocarbonyl)amino]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(1,4-oxazepan-4-ylmethyl)phenyl]thiophene-3-carboxamide;-   (1S)-2-((aminocarbonyl)amino)-5-(4-(1-{morpholin-4-yl}ethyl)phenyl)thiophene-3-carboxamide;-   2-((aminocarbonyl)amino)-5-(4-(1-methyl-1-{morpholin-4-yl}ethyl)phenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-((4-methylpiperazin-1-yl)methyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-((2-ethoxycarbonylpiperidin-1-yl)methyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-((3-diethylaminocarbonylpiperidin-1-yl)methyl)phenyl]-thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-({(2-hydroxyethyl)piperazin-1-yl}methyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-4-methyl-5-{4-[4-morpholino]methylphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-((4-hydroxypiperidin-1-yl)methyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(2-piperazin-1-ylphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(4-methylpiperazin-1-yl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[3-methylamino)pyrrolidin-1-yl]phenyl}thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(cyclopentyloxy)-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-{piperidin-1-yl}ethoxy)-4-pyrrolidin-1-ylphenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-piperidin-1-yl-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(2-methoxyethoxy)-2-(2-piperidin-1-ylethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-morpholin-4-yl-2-(2-piperidin-1-ylethoxy)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-hydroxyethoxy)phenyl]thiophene-3-carboxamide;-   (3R)-2-[(aminocarbonyl)amino]-5-{2-[tetrahydrofuran-3-yloxy]phenyl}-3-thiophenecarboxamide;-   (3S)-2-[(aminocarbonyl)amino]-5-{2-[tetrahydrofuran-3-yloxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(tetrahydropyran-4-yloxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[cyclopropylmethoxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[cyclopentyloxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-ethylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-tert-butyloxycarbonyl-3-pyrrolidinyl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(pyrrolidin-3-yloxy)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-methylpiperidin-2-yl)methoxy]phenyl}-3-thiophenecarboxamide;-   (2S)-2-[(aminocarbonyl)amino]-5-(2-{[1-methylpyrrolidin-2-yl]methoxy}phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-{[1-(2-methoxyethyl)pyrrolidin-3-yl]oxy}phenyl)-3-thiophenecarboxamide;-   (2R)-2-[(aminocarbonyl)amino]-5-(2-{[1-methylpyrrolidin-2-yl]methoxy}phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-(2,2,6-trimethylpiperidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{5-chloro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4-fluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{4,5-difluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-methylphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{5-cyano-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-methoxyphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{3,5-difluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-3-methoxyphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-trifluoromethylphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-4-trifluoromethylphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-4-methoxyphenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{5-fluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-3-(morpholin-4-ylmethyl)phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-(2-{[(1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}phenyl)-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-cyclopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-methylpiperidin-4-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(2-{morpholin-4-yl}acetyl)phenyl]3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-{2-(4-hydroxy-1-piperidinyl)ethoxy}phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[2-(3-pyrrolin-1-yl)ethoxy]phenyl}thiophene-3-carboxamide;-   cis/trans-2-[(aminocarbonyl)amino]-5-{2-[2-(2,5-dimethyl-3-pyrrolin-1-yl)ethoxy]phenylthiophene-3-carboxamide;-   (2S)-2-[(aminocarbonyl)amino]-5-[4-(2-methoxymethylpyrrolidin-1-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(4-aminocarbonylpiperidin-1-ylmethyl)phenylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(3-hydroxymethylpiperidin-1-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(4-hydroxymethylpiperidin-1-ylmethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(3-{morpholin-4-yl}pyrrolidin-1-yl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{2-[(1S,4S)-2,5-diazabicyclobicyclo[2.2.1]hept-2-yl]phenyl}thiophene-3-carboxamide;

and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the term “C₁-C₆ alkyl” referred to hereindenotes a straight or branched chain alkyl group having from 1- to 6carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and t-butyl. The terms “C₁-C₂ alkyl” and“C₁-C₄ alkyl” are to be interpreted analogously.

Unless otherwise indicated, the term “C₂-C₃ alkenyl” referred to hereindenotes a straight or branched chain alkyl group having 2 or 3 carbonatoms incorporating at least one carbon-carbon double bond. Examples ofsuch groups include ethenyl and propenyl. The term “C₂-C₆ alkenyl” is tobe interpreted analogously.

Unless otherwise indicated, the term “C₂-C₃ alkynyl” referred to hereindenotes a straight chain alkyl group having 2 or 3 carbon atomsincorporating one carbon-carbon triple bond. Examples of such groupsinclude ethynyl and propynyl. The term “C₂-C₆ alkynyl” is to beinterpreted analogously.

Unless otherwise indicated, the term “C₃-C₆ cycloalkyl” referred toherein denotes a saturated carbocyclic ring having from 3 to 6 carbonatoms. Examples of such groups include cyclopropyl, cyclopentyl andcyclohexyl.

Unless otherwise indicated, the term “C₁-C₄ alkoxy” referred to hereindenotes a straight or branched chain alkoxy group having 1 to 4 carbonatoms. Examples of such groups include methoxy, ethoxy and isopropoxy.The terms “C₁-C₂ alkoxy” and “C₁-C₆ alkoxy” are to be interpretedanalogously.

Unless otherwise indicated, the term “C₁-C₂ alkanoyl” referred to hereindenotes a formyl or acetyl group.

Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

Examples of a 5- to 7-membered heteroaromatic ring containing one tothree heteroatoms selected independently from O, N and S include furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine andpyrazine.

Examples of a 3- to 8-membered saturated or partially unsaturatedmonocyclic or saturated bicyclic ring system optionally incorporatingone or two heteroatoms selected independently from O, N and S, andoptionally incorporating a carbonyl group include cyclopropyl,cyclopentyl, cyclohexyl, tetrahydrofuran, tetrahydropyran, pyrrolidine,3-pyrroline, piperidine, piperazine, 8-oxa-3-azabicyclo[3.2.1]octane,pyrrolidone, 2-oxa-5-azabicyclo[2.2.1]heptane, 1,4-oxazepane,2,5-diazabicyclo[2.2.1]heptane, piperidone and morpholine.

Examples of a 5- or 6-membered saturated azacyclic ring optionallycontaining a further O, S or NR group include pyrrolidine, piperidine,piperazine and morpholine.

According to the invention there is also provided a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof which comprises:

(a) reaction of a compound of formula (II):

wherein A, R², R³ and n are as defined in formula (I) with an isocyanateor an isothiocyanate or an acyl derivative, R¹—CO-L where L is a leavinggroup; or

(b) reaction of compound of formula (III)

wherein R³, n and A are as defined in formula (I)

with a compound of formula (IV)

wherein X, R¹ and R² are as defined in formula (I) and LG represents aleaving group; or

(c) reaction of compound of formula (V)

wherein R³, n and A are as defined in formula (I) and LG represents aleaving group, with a compound of formula (VI)

wherein X, R¹ and R² are as defined in formula (I);

and where necessary converting the resultant compound of formula (I), oranother salt thereof, into a pharmaceutically acceptable salt thereof,or converting the resultant compound of formula (I) into a furthercompound of formula (I); and where desired converting the resultantcompound of formula (I) into an optical isomer thereof.

In process (a), suitable isocyanate reagents includetrimethylsilylisocyanate, trimethylsilylisothiocyanate,chlorosulphonylisocyanate, trichloroacetylisocyanate and sodiumisocyanate. The reaction with trimethylsilylisocyanate ortrimethylsilylisothiocyanate can be carried out in a solvent such asdichloromethane/dimethylformamide at a suitable elevated temperature,for example, at the reflux temperature of the reaction mixture. Thereaction with chlorosulphonylisocyanate can be carried out in a solventsuch as toluene at ambient temperature. The reaction with sodiumisocyanate can be carried out in a suitable solvent system such asaqueous acetic acid at ambient temperature. Thetrichloroacetylisocyanate reaction can be carried out in a suitablesolvent system such as acetonitrile at ambient temperature, andsubsequently treating the mixture with ammonia to give compounds of thegeneral formula (I). Suitable acyl derivatives of formula R¹—CO-Linclude acyl halides, particularly acyl chlorides, and acid anhydrides.Reactions with such acyl derivatives are generally carried out atambient temperature in a suitable solvent such as pyridine, or in asolvent such as dichloromethane in the presence of a suitable base suchas triethylamine or pyridine.

Compounds of formula (I) wherein X represents O may subsequently beconverted into corresponding compounds of formula (I) wherein Xrepresents S by reaction with, for example, Lawesson's reagent.

In processes (b) and (c), the compounds of formulae (III) and (IV) or offormulae (V) and (VI) are reacted together under catalysis provided by acomplex of a transition metal such as palladium or nickel. In compoundsof formulae (III) and (VI), under appropriate conditions, “metal” can bea metal or semi-metal such as magnesium, zinc, copper, tin, silicon,zirconium, aluminium or boron. Suitable leaving groups include iodo,bromo, chloro, triflate or phosphonate.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at an appropriate stage, theaddition and removal of one or more protecting groups.

The protection and deprotection of functional groups is fully describedin ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 3rdedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1999).

The present invention includes compounds of formula (I) in the form ofsalts, in particular acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

Salts of compounds of formula (I) may be formed by reacting the freebase, or a salt, enantiomer or racemate thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

Compounds of formula (II) can be prepared by standard chemistrydescribed in the literature [for example, J. Het. Chem. 36, 333 (1999)]or by reaction of compounds of formula (VII):

where A, R², R³ and n are as defined in formula (I), and L represents aleaving group, with ammonia. Suitable groups L include halogen, inparticular chloro.

Compounds of formula (VII) where L is halo can be prepared from thecorresponding compound of formula (VII):

where A, R², R³ and n are as defined in formula (I), by treating with ahalogenating agent such as thionyl chloride.

Compounds of formulae (III), (IV), (V), (VI) and (VI) are commerciallyavailable or can be prepared using standard chemistry as exemplifiedherein.

Certain novel intermediate compounds form a further aspect of theinvention.

The compounds of formula (I) have activity as pharmaceuticals, inparticular as IKK-2 enzyme inhibitors, and may be used in the treatment(therapeutic or prophylactic) of conditions/diseases in human andnon-human animals in which inhibition of IKK-2 is beneficial. Examplesof such conditions/diseases include inflammatory diseases or diseaseswith an inflammatory component. Particular diseases include inflammatoryartritides including rheumatoid arthritis, osteoarthritis, spondylitis,Reiters syndrome, psoriatic arthritis, lupus and bone resorptivedisease; multiple sclerosis, inflammatory bowel disease includingCrohn's disease; asthma, chronic obstructive pulmonary disease,emphysema, rhinitis, myasthenia gravis, Graves' disease, allograftrejection, psoriasis, dermatitis, allergic disorders, immune complexdiseases, cachexia, ARDS, toxic shock, heart failure, myocardialinfarcts, atherosclerosis, reperfusion injury, AIDS, cancer anddisorders characterised by insulin resistance such as diabetes,hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycysticovarian disease, hypertension, cardiovascular disease and Syndrome X.

The reported roles of NF-κB in both oncogenesis and chemoresistancesuggest that inhibition of this pathway through the use of an IKK2inhibitor, such as a small molecule IKK2 inhibitor, could provide anovel monotherapy for cancer and/or an important adjuvant therapy forthe treatment of chemoresistant tumours.

We are particularly interested in diseases selected from asthma,rheumatoid arthritis, psoriasis, inflammatory bowel disease includingCrohn's disease, multiple sclerosis, chronic obstructive pulmonarydisease, bone resorptive disease, osteoarthritis, diabetes/glycaemiccontrol and cancer.

Thus, the present invention provides a compound of formula (I), or apharmaceutically acceptable salt thereof, as hereinbefore defined foruse in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,as hereinbefore defined in the manufacture of a medicament for use intherapy.

In a still further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,as hereinbefore defined in the manufacture of a medicament for thetreatment of diseases or conditions in which modulation of the IKK-2enzyme activity is beneficial.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

The invention still further provides a method of treating an IKK-2mediated disease which comprises administering to a patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, as hereinbefore defined.

The invention also provides a method of treating an inflammatorydisease, especially asthma, rheumatoid arthritis or multiple sclerosis,in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Depending onthe mode of administration, the pharmaceutical composition willpreferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,as hereinbefore defined, with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally. Conventional procedures for the selection andpreparation of suitable pharmaceutical formulations are described in,for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E.Aulton, Churchill Livingstone, 1988.

The invention is illustrated, but in no way limited, by the followingexamples:

Example 12-[(Aminocarbonyl)amino]methyl-5-(4-biphenyl)-3-thiophenecarboxamide a)2-Amino-4-methyl-5-(4-biphenyl)-3-thiophenecarboxamide

4-Biphenyl acetone (2.0 g), cyanoacetamide (0.88 g), sulphur (0.37 g)and morpholine (1 ml) in ethanol (5 ml) were stirred and heated at 55°C. for 6 h. The reaction mixture was cooled and filtered before addingto water (150 ml). The precipitated solid was filtered off, washed withwater and then dried. The product was then triturated with ether andcollected.

MS (ES) 309 (M+H)⁺.

¹H NMR (DMSO-D6) 2.3 (s, 3H), 6.8 (s, 2H), 6.9 (s, 2H), 7.4 (m, 5H), 7.6(m, 4H).

b)2-[(Aminocarbonyl)amino]-4-methyl-5-(4-biphenyl)-3-thiophenecarboxamide

2-Amino-4-methyl-5-(4-biphenyl)-3-thiophenecarboxamide (0.44 g) wasdissolved in tetrahydrofuran (10 ml), cooled to 0° C. andtrichloroacetylisocyanate (0.11 ml) added dropwise with stirring.Stirring was continued for a further 30 minutes at room temperature andthen a solution of ammonia in methanol (8 ml of a 10% solution) wasadded and stirring was continued for a further 3 h. The solvent wasevaporated and the residue treated with ethyl acetate and the productfiltered off.

MS (ES) 350 (M−H)⁻.

¹H NMR (DMSO-D6) 2.2 (s, 3H), 6.7 (s, 2H), 7.4 (m, 2H), 7.45 (m, 4H),7.7 (m, 5H), 7.8 (m, 1H).

Example 22-[(Aminocarbonyl)amino]methyl-5-(4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl acetone using the method ofExample 1.

MS (ES) 399 (M−H)⁻.

¹H NMR (DMSO-D6) 2.2 (s, 6H), 2.4 (s, 3H), 4.95 (s, 2H), 6.65 (m, 2H),7.0 (m, 3H), 10.04 (brs, 1H).

b) 4-[(3,5-Dimethylisoxazol-4-yl)methoxy]phenyl acetone

A mixture of 4-hydroxyphenyl acetone (1.5 g),4-chloromethyl-3,5-dimethylisoxazole (1.6 g) and potassium carbonate(1.5 g) in dimethylformamide (10 ml) was heated and stirred at 60° C.for 18 h. After cooling, the mixture was poured into water and extractedtwice with ethyl acetate. The combined solvent phase was washed twicewith brine, dried (magnesium sulphate) and then evaporated. Theresultant oil was chromatographed on silica using isohexane to 20% ethylacetate in isohexane mixtures to give the title compound (2.5 g).

MS (ES) 259 (M−H)⁻.

¹H NMR (DMSO-D6) 2.05 (s, 3H), 2.2 (s, 3H), 2.4 (s, 3H), 3.6 (s, 2H),4.85 (s, 2H), 6.9 (d, 2H), 7.1 (d, 2H).

Example 32-[(Aminocarbonyl)amino]-4-methyl-5-(4-[(4-chlorophenyl)methoxy]phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from4-[(4-chlorophenyl)methoxy]phenyl acetone by the method of Example 1.

MS (ES) 414 (M−H)⁻.

¹H NMR (DMSO-D6) 2.2 (s, 3H), 5.1 (s, 2H), 6.7 (br, 2H), 7.05 (d, 2H),7.25 (m, 3H), 7.4 (m, 5H), 10.04 (m, 1H).

b) 4-[(4-Chlorophenyl)methoxy]phenyl acetone

Prepared from 4-chlorobenzyl chloride and 4-hydroxyphenyl acetone by themethod of Example 2 (b).

MS (ES) 275 (M+H)⁺.

¹H NMR (DMSO-D6) 2.05 (s, 3H), 3.6 (s, 2H), 5.0 (s, 2H), 6.9 (d, 2H),7.05 (d, 2H), 7.4 (m, 4H).

Example 42-[(Aminocarbonyl)amino]-4-methyl-5-(4-[(5-chlorothien-2-yl)methoxy]phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from4-[(5-chlorothien-2-yl)methoxy]phenyl acetone by the method of Example1.

MS (ES) 420 (M−H)⁻.

¹H NMR (DMSO-D6) 2.2 (s, 3H), 5.2 (s, 2H), 6.7 (br, 2H), 7.1 (m, 4H),7.3 (m, 4H), 10.04 (m, 1H).

b) 4-[(5-Chlorothien-2-yl)methoxy]phenyl acetone

Prepared by the method of Example 2 (b) from2-chloromethyl-5-chlorothiophene and 4-hydroxyphenyl acetone.

MS (ES) 281 (M+H)⁺.

Example 52-[(Aminocarbonyl)amino]-4-methyl-5-{4-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from2-amino-4-methyl-5-{4-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamideby the method of Example 1 (b).

MS (ES) 459 (M+H)⁺.

¹H NMR (DMSO-D6) 1.02 (s, 12H), 1.58-1.30 (m, 6H), 2.23 (s, 3H), 3.84(t, 2H), 2.82 (t, 2H), 6.71 (bs, 2H), 6.96 (d, 2H), 7.23 (d, 2H), 7.26(bs, 2H), 10.04 (s, 1H).

b)2-Amino-4-methyl-5-{4-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamide

Prepared from 4-[2-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxy]phenylacetone by the method of Example 1 (a).

MS (ES) 416 (M+H)⁺.

¹H NMR (DMSO-D6) 1.02 (s, 12H), 1.30-1.41 (m, 4H), 1.45-1.55 (m, 2H),2.19 (s, 3H), 2.80 (t, 2H), 3.83 (t, 2H), 6.75 (bs, 2H), 6.84 (s, 2H),6.93 (d, 2H), 7.18 (d, 2H).

c) 4-[2-(2,2,6,6-Tetramethylpiperidin-1-yl)ethoxy]phenyl acetone

Prepared from 2-(2,2,6,6-tetramethylpiperidin-1-yl)ethyl chloride and4-hydroxyphenylacetone in a similar manner to Example 2 (b).

MS (ES) 318 (M+H)⁺.

¹H NMR (DMSO-D6) 1.05 (s, 12H), 1.35-1.49 (m, 4H), 1.49-1.61 (m, 2H),2.13 (s, 3H), 2.86 (t, 2H), 3.61 (s, 2H), 3.85 (t, 2H), 6.85 (d, 2H),7.09 (d, 2H).

Example 62-[(Aminocarbonyl)amino]-4-methyl-5-(4-[(thiazol-4-yl)methoxy]phenyl-3-thiophenecarboxamide

a) The title compound was prepared from2-amino-4-methyl-5-(4-[(thiazol-4-yl)methoxy]phenyl)-3-thiophenecarboxamideby the method of Example 1.

MS (ES) 389 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz, δ 2.23 (s, 3H), 5.23 (s, 2H), 6.70 (s, 2H),7.09 (d, 2H), 7.27 (d, 2H), 7.0-7.5 (bs, 3H), 7.79 (s, 1H), 9.11 (s,1H).

b)2-Amino-4-methyl-5-(4-[(thiazol-4-yl)methoxy]phenyl)-3-thiophenecarboxamide

Prepared from 4-[(thiazol-4-yl)methoxy]phenyl acetone by the method ofExample 1.

MS (ES) 329 (M−NH3)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.20 (s, 3H), 5.22 (s, 2H), 6.77 (s, 2H),6.85 (s, 2H), 7.05 (d, 2H), 7.20 (d, 2H), 7.77 (s, 1H), 9.11 (s, 1H).

c) 4-[(Thiazol-4-yl)methoxy]phenyl acetone

Prepared from 4-chloromethylthiazole and 4-hydroxyphenylacetone by themethod of Example 1.

MS (ES) 248 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.13 (s, 3H), 3.63 (s, 2H), 5.26 (s, 2H),6.79 (d, 2H), 7.12 (d, 2H), 7.38 (s, 1H), 8.83 (s, 1H).

Example 72-[(Aminocarbonyl)amino]-4-methyl-5-(4-[(1,2,5-thiadiazol-3-yl)methoxy]phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from2-amino-4-methyl-5-(4-[(1,2,5-thiadiazol-3-yl)methoxy]phenyl)-3-thiophenecarboxamideby the method of Example 1.

MS (ES) 388 M⁻.

¹H NMR (DMSO-D6) 300 MHz δ 2.22 (s, 3H), 5.46 (s, 2H), 7.10 (d, 2H),7.12 (bs, 2H), 7.23 (s, 2H), 7.30 (d, 2H), 8.97 (s, 1H).

b)2-Amino-4-methyl-5-(4-[(1,2,5-thiadiazol-3-yl)methoxy]phenyl)-3-thiophenecarboxamide

Prepared from 4-[(1,2,5-thiadiazol-3-yl)methoxy]phenyl acetone by themethod of Example 1.

MS (ES) 347 M⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.20 (s, 3H), 5.45 (s, 2H), 6.76 (s, 2H),7.08 (d, 2H), 7.23 (d, 2H), 8.95 (s, 1H).

c) 4-[(1,2,5-Thiadiazol-3-yl)methoxy]phenyl acetone

Prepared from 3-bromomethyl-1,2,5-thiadiazole and 4-hydroxyphenylacetoneby the method of Example 1.

MS (ES)249 (MH)⁺.

¹H NMR CDCl₃ 300 MHz δ 2.15 (s, 3H), 3.63 (s, 2H), 5.36 (s, 2H), 6.96(d, 2H), 7.14 (d, 2H), 8.68 (s, 1H).

Example 82-[(Aminocarbonyl)amino]-4-methyl-5-(4-[(1-methylperhydroazepin-3-yl)oxy]phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from2-amino-4-methyl-5-(4-[(1-methylperhydroazepin-3-yl)oxy]phenyl)-3-thiophenecarboxamideby the method of Example 1.

MS (ES) 403 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.62 (m, 1H), 1.72 (m, 2H), 2.00 (m, 1H),2.35-2.60 (m, 3H), 2.70 (m, 2H), 2.90 (m, 1H), 4.56 (m, 1H), 6.70 (s,2H), 6.95 (d, 2H), 7.24 (bs, 2H; d, 2H), 10.04 (s, 1H).

b)2-Amino-4-methyl-5-(4-[(1-methylperhydroazepin-3-yl)oxy]phenyl)-3-thiophenecarboxamide

Prepared from 4-[(1-methylperhydroazepin-3-yl)oxy]phenyl acetone by themethod of Example 1.

MS (ES) 360 (MH)⁺.

¹H NMR CDCl₃ 300 MHz δ 2.03 (m, 2H), 2.12 (m, 2H), 2.56 (m, 1H), 2.70(m, 3H), 2.90 (m, 2H), 4.50 (m, 1H), 5.53 (s, 2H), 6.20 (s, 2H), 6.89(d, 2H), 7.22 (d, 2H).

c) 4-[(1-Methylperhydroazepin-3-yl)oxy]phenyl acetone

Prepared from 1-methyl-2-chloromethylpiperidine and4-hydroxyphenylacetone by the method of Example 1 to give a mixture(50:50) of the above product and4-([1-methyl-piperidin-2-yl]methoxy)phenyl acetone.

MS (ES) 262 (MH)⁺.

Example 92-[(Aminocarbonyl)amino]-5-[6-(pyrrolidin-1-yl)pyridin-3-yl]-3-thiophenecarboxamidea) 2-Amino-3-thiophenecarboxamide

A suspension of 2,5-dihydroxy-1,4-dithiane (25 g) and cyanoacetamide(19.3 g) in ethanol (120 ml) was stirred and heated to 50° C.Triethylamine (9.2 ml) was added over 15 minutes and the mixture wasstirred at 50° C. for a further 2 h. After cooling in ice, the solid wasfiltered off and dried (21.4 g).

MS (ES) 143 (M+H)⁺.

b) 2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide

2-Amino-3-thiophenecarboxamide (0.44 g) was suspended in acetonitrile(25 ml) and trichloroacetylisocyanate (0.2 ml) added dropwise withstirring over 10 minutes. Stirring was continued for a further 3 h atroom temperature and then a solution of ammonia in methanol (10 ml of a2M solution) was added and stirring continued for a further 2 h. Thesolvent was evaporated and the residue treated with water. The resultantsolid was filtered off and washed with more water. Trituration withether gave the title urea (0.2 g).

MS (ES) 186 (M+H)⁺.

c) 2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide

2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) was dissolved inacetic acid (20 ml) and a solution of bromine (0.35 ml) in acetic acid(5 ml) was added over 5 minutes with rapid stirring. The mixture wasstirred for 90 minutes and then added to water (50 ml). The product wasfiltered off and washed with water and dried under vacuum (0.55 g).

MS (ES) 262/264 (M−H)⁻.

¹H NMR (DMSO-D6) 7.15 (m, 1H), 7.35 (m, 1H), 7.8 (s, 1H), 7.9 (m, 1H),10.63 (brs, 1H).

d) 5-Iodo-2-pyrrolidin-1-yl pyridine

Pyrrolidine (1.74 ml) was added to 2-chloro-5-iodopyridine (1 g) indimethylacetamide (5 ml) and the solution heated at 120° C. for 4 h.After cooling, the reaction mixture was poured into water (60 ml) andthe solid precipitate collected by filtration. Recrystallisation fromethyl acetate gave the product as off-white needles (0.33 g); theremaining material was adsorbed onto silica and purified by columnchromatography eluting with 0 to 3% ethyl acetate in hexane to give awhite solid (0.65 g).

MS (ES) 275 (M+H)⁺.

¹H NMR (DMSO-D6) 1.84-1.98 (m, 4H), 3.24-3.37 (m, 4H), 6.33 (d, 1H),7.67 (dd, 1H), 8.16 (d, 1H).

e)2-[(Aminocarbonyl)amino]-5-[6-(pyrrolidin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide

2-Pyrrolidinyl-5-iodopyridine (0.778 g) was stirred in tetrahydrofuran(20 ml) under argon. Triisopropylborate (1.31 ml) was added the solutionwas cooled to −78° C. n-Butyl lithium (2.66 ml, 1.6M solution in hexane)was added dropwise. The reaction mixture was stirred at −78° C. for 5minutes then allowed to warm to room temperature and stirred for afurther 30 minutes. The mixture was then evaporated to dryness.1,2-Dimethoxyethane (20 ml) was added to the residue and purged with astream of argon. 2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide(0.250 g) was then added followed by saturated aqueous sodium hydrogencarbonate (7 ml) and Pd(PPh₃)₄ (100 mg). The mixture was heated at 90°C. under argon for 18 h. After cooling, the solvent was removed in vacuoand the residue taken up in 2M aqueous sodium hydroxide (30 ml) and 10%methanol in dichloromethane (40 ml). The layers were separated and theorganic phase extracted with a further portion of 2M aqueous sodiumhydroxide (20 ml). The solid remaining undissolved at the interface wascollected by filtration, washed with water and dichloromethane and driedto give the product as a pale brown solid (0.219 g).

MS (ES) 332 (M+H)⁺.

¹H NMR DMSO-D6) 1.83-2.01 (m, 4H), 3.28-3.46 (m, 4H), 6.47 (d, 1H), 6.87(bs, 2H), 7.23 (bs, 1H), 7.43 (s, 1H), 7.58 (bs, 1H), 7.58 (dd, 1H),8.20 (d, 1H), 10.91 (s, 1H).

Example 102-[(Aminocarbonyl)amino]-5-[6-(2,2-difluoroethoxy)pyridin-3-yl]-3-thiophenecarboxamide

a) 5-Bromo-2-(2,2-difluoroethoxy)pyridine (0.541 g) was stirred in (10ml) under argon. Triisopropylborate (1.05 ml) was added and the solutionwas cooled to −78° C. Butyl lithium (2.13 ml, 1.6M solution in hexane)was added dropwise. The mixture was then allowed to warm to roomtemperature and stirring continued for 1 h. The tetrahydrofuran wasremoved in vacuo, dimethoxyethane (12 ml) was added and the mixture waspurged with argon.2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide was added,followed by sodium hydrogen carbonate (3.5 ml of a saturated aqueoussolution) and Pd(PPh₃)₄ (100 mg). The mixture was heated at 90° C. for 6h under argon, then allowed to cool and stirred at room temperature for18 h. The solvent was removed in vacuo and the residue taken up in 2Maqueous sodium hydroxide (30 ml) and 10% methanol in dichloromethane (40ml). The layers were separated and the organic phase washed with afurther portion of 2M aqueous sodium hydroxide (20 ml). The combinedaqueous layers were washed with dichloromethane (40 ml), then filteredand the filtrate neutralised with 6M aqueous hydrochloric acid. Theresultant precipitate was collected by filtration, washed with water anddried to give the product as a pale brown solid (146 mg).

MS (ES) 343 (M+H)⁺.

¹H NMR (DMSO-D6) 4.57 (td, 2H), 6.38 (tt, 1H), 6.94 (bs, 2H), 6.96 (d,1H), 7.30 (bs, 1H), 7.63 (bs, 1H), 7.67 (s, 1H), 7.87 (dd, 1H), 8.30 (d,1H), 10.97 (s, 1H).

b) 5-Bromo-2-(2,2-difluoroethoxy)pyridine

2,2-Difluoroethanol (0.40 ml) was added dropwise to a suspension ofsodium hydride (0.270 g) in dimethylformamide (5 ml) cooled in anice-bath under argon. The mixture was stirred at room temperature for 40minutes, then re-cooled in an ice-bath. A solution of2,5-dibromopyridine (1 g) in dimethylformamide (5 ml) was added. Thesolution was then heated at 65° C. under argon for 18 h, allowed to cooland diluted with water (50 ml). The aqueous phase was extracted threetimes with ethyl acetate. The combined extracts were washed with water,brine, dried over magnesium sulphate, filtered and evaporated. Theproduct was purified by column chromatography eluting with hexane togive a colourless oil (0.946 g).

MS (CI) 238 (M+H)⁺.

¹H NMR (DMSO-D6) 4.50 (td, 2H), 6.10 (tt, 1H), 6.74 (d, 1H), 7.70 (dd,1H), 8.18 (d, 1H).

Example 112-[(Aminocarbonyl)amino]-5-[6-(piperidin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from 5-iodo-2-piperidinylpyridine ina similar manner to Example 10 (a).

MS (ES) 346 (M+H)⁺.

¹H NMR (DMSO-D6) 1.44-1.66 (m, 6H), 3.44-3.58 (m, 4H), 6.84 (d, 1H),6.90 (bs, 2H), 7.24 (bs, 1H), 7.47 (s, 1H), 7.56 (bs, 1H), 7.60 (dd,1H), 8.23 (d, 1H).

b) 5-Iodo-2-piperidinylpyridine

Prepared from 2-chloro-5-iodopyridine and piperidine by the method ofExample 9 (d).

MS (ES) 289 (M+H)⁺.

¹H NMR (DMSO-D6) 1.43-1.64 (m, 6H), 3.41-3.52 (m, 4H), 6.69 (d, 1H),7.68 (dd, 1H), 8.20 (d, 1H).

Example 122-[(Aminocarbonyl)amino]-5-[6-(cyclopentyloxy)pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(cyclopentyloxy)pyridine in a similar manner to Example 10(a).

MS (ES) 347 (M+H)⁺.

¹H NMR (DMSO-D6) 1.46-1.78 (m, 6H), 1.83-2.02 (m, 2H), 5.30-5.40 (m,1H), 6.78 (d, 1H), 6.93 (bs, 2H), 7.29 (bs, 1H), 7.60 (bs, 1H), 7.60 (s,1H), 7.76 (dd, 1H), 8.25 (d, 1H), 10.95 (s, 1H).

b) 5-Bromo-2-(cyclopentyloxy)pyridine

Prepared from 2,5-dibromopyridine and cyclopentanol by the method ofExample 10 (b).

MS (EI) 241 (M)⁺.

¹H NMR (DMSO-D6) 1.54-2.05 (m, 8H), 5.28-5.37 (m, 1H), 6.58 (d, 1H),7.60 (dd, 1H), 8.17 (d, 1H).

Example 132-[(Aminocarbonyl)amino]-5-[6-(4-ethanesulfonylpiperazin-1-yl)pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(4-ethanesulphonylpiperazin-1-yl)pyridine in a similar mannerto Example 9 (e).

MS (ES) 439 (M+H)⁺.

¹H NMR (DMSO-D6) 1.21 (t, 3H), 3.07 (q, 2H), 3.18-3.30 (m, 4H),3.53-3.66 (m, 4H), 6.90 (bs, 2H), 6.94 (d, 1H), 7.30 (bs, 1H), 7.54 (s,1H), 7.60 (bs, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 10.94 (s, 1H).

b) 5-Bromo-2-(4-ethanesulfonylpiperazin-1-yl)pyridine

2,5-Dibromopyridine (1 g) was heated in dimethylacetamide (2.5 ml) withethanesulfonylpiperazine (0.752 g) and diisopropylethylamine (1.84 ml)at 120° C. for 18 h. After cooling, the reaction mixture was poured intowater (30 ml) and the precipitated solid was collected by filtration.The product was purified by column chromatography eluting withdichloromethane (0.50 g).

MS (ES) 334 (M+H)⁺.

¹H NMR (DMSO-D6) 1.40 (t, 3H), 2.98 (q, 2H), 3.35-3.43 (m, 4H),3.57-3.66 (m, 4H), 6.56 (d, 1H), 7.56 (dd, 1H), 8.21 (d, 1H).

Example 142-[(Aminocarbonyl)amino]-5-[6-[(tetrahydrofuran-2-yl)methoxy]pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[(tetrahydrofuran-2-yl)methoxy]pyridine in a similar manner toExample 10 (a).

MS (ES) 363 (M+H)⁺.

¹H NMR (DMSO-D6) 1.55-2.05 (m, 4H), 3.59-3.82 (m, 2H), 4.07-4.30 (m,3H), 6.85 (d, 1H), 6.94 (bs, 2H), 7.29 (bs, 1H), 7.60 (bs, 1H), 7.60 (s,1H), 7.80 (dd, 1H), 8.25 (d, 1H), 10.96 (s, 1H).

b) 5-Bromo-2-[(tetrahydrofuran-2-yl)methoxy]pyridine

Prepared from 2,5-dibromopyridine and tetrahydrofuran-2-methanol by themethod of Example 10(b).

MS (CI) 258 (M+H)⁺.

¹H NMR (DMSO-D6) 1.63-2.12 (m, 4H), 3.77-3.98 (m, 2H), 4.14-4.38 (m,3H), 6.71 (d, 1H), 7.63 (dd, 1H), 8.15 (d, 1H).

Example 152-[(Aminocarbonyl)amino]-5-{3-[6-(furan-2-ylmethoxy)]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(furan-2-ylmethoxy)-pyridine in a similar manner to Example 10(a).

MS (ES) 359 (M+H)⁺.

¹H NMR (DMSO-D6) 5.30 (s, 2H), 6.44 (m, 1H), 6.55 (d, 1H), 6.87 (d, 1H),6.94 (bs, 2H), 7.29 (bs, 1H), 7.62 (bs, 1H), 7.62 (s, 1H), 7.67 (d, 1H),7.82 (dd, 1H), 8.30 (d, 1H), 10.96 (s, 1H).

b) 5-Bromo-2-(furan-2-ylmethoxy)-pyridine

Prepared from 2,5-dibromopyridine and 2-furanmethanol by the method ofExample 10(b).

MS (EI) 253 (M)⁺.

¹H NMR (DMSO-D6) 5.27 (s, 2H), 6.44 (t, 1H), 6.53 (d, 1H), 6.84 (d, 1H),7.67 (s, 1H), 7.89 (dd, 1H), 8.29 (d, 1H).

Example 162-[(Aminocarbonyl)amino]-5-{3-[6-(4-acetyl)piperazin-1-yl]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from1-[4-(5-bromo-pyridin-2-yl)piperazin-1-yl]ethanone in a similar mannerto Example 10(a) but using t-butyl lithium (2 eq.) in place of n-butyllithium.

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 2.03 (s, 3H), 3.43-3.61 (m, 8H), 6.90 (bs, 2H), 6.90(d, 1H), 7.26 (bs, 1H), 7.52 (s, 1H), 7.60 (bs, 1H), 7.67 (dd, 1H), 8.27(d, 1H), 10.93 (s, 1H).

b) 1-[4-(5-Bromo-pyridin-2-yl)piperazin-1-yl]ethanone

Prepared from 2,5-dibromopyridine and 1-acetylpiperazine by the methodof Example 13 (b).

MS (ES) 284 (M+H)⁺.

¹H NMR (DMSO-D6) 2.13 (s, 3H), 3.43-3.50 (m, 2H), 3.52-3.64 (m, 4H),3.68-3.78 (m, 2H), 6.54 (d, 1H), 7.56 (dd, 1H), 8.20 (d, 1H).

Example 17(R)-2-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from(R)-5-bromo-2-(tetrahydrofuran-3-yloxy)-pyridine in a similar manner toExample 10 (a).

MS (ES) 349 (M+H)⁺.

¹H NMR (DMSO-D6) 1.90-2.04 (m, 1H), 2.13-2.30 (m, 1H), 3.68-3.95 (m,4H), 5.45-5.54 (m, 1H), 6.85 (d, 1H), 6.94 (bs, 2H), 7.30 (bs, 1H), 7.60(bs, 1H), 7.60 (s, 1H), 7.80 (dd, 1H), 8.25 (d, 1H), 10.95 (s, 1H).

b) (R)-5-Bromo-2-(tetrahydrofuran-3-yloxy)-pyridine

Prepared from 2,5-dibromopyridine and (R)-3-hydroxytetrahydrofuran bythe method of Example 10 (b).

MS (ES) 244 (M+H)⁺.

¹H NMR (DMSO-D6) 2.03-2.33 (m, 2H), 3.83-4.07 (m, 4H), 5.46-5.54 (m,1H), 6.65 (d, 1H), 7.63 (dd, 1H), 8.16 (d, 1H).

Example 182-[(Aminocarbonyl)amino]-5-{3-[6-(1-isopropyl-pyrrolidin-3-yloxy)]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(1-isopropyl-pyrrolidin-3-yloxy)-pyridine in a similar mannerto Example 10 (a).

MS (ES) 390 (M+H)⁺.

¹H NMR (DMSO-D6) 0.99 (d, 3H), 1.02 (d, 3H), 1.69-1.87 (m, 1H),2.15-2.94 (m, 6H), 5.28-5.38 (m, 1H), 6.83 (d, 1H), 7.94 (bs, 2H), 7.29(bs, 1H), 7.60 (bs, 1H), 7.60 (s, 1H), 7.77 (dd, 1H), 8.25 (d, 1H),10.95 (s, 1H).

b) 5-Bromo-2-(1-isopropyl-pyrrolidin-3-yloxy)-pyridine

Prepared from 2,5-dibromopyridine and 1-isopropylpyrrolidin-3-ol by themethod of Example 10 (b).

MS (ES) 285 (M+H)⁺.

¹H NMR (DMSO-D6) 1.10 (d, 3H), 1.12 (d, 3H), 1.88-2.02 (m, 1H),2.25-2.53 (m, 3H), 2.80-2.96 (m, 3H), 5.32-5.43 (m, 1H), 6.64 (d, 1H),7.60 (dd, 1H), 8.15 (d, 1H).

Example 192-[(Aminocarbonyl)amino]-5-{3-[6-(1-t-butyloxycarbonyl-piperidin-4-yloxy]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(1-t-butyloxycarbonyl-piperidin-4-yloxy)-5-bromopyridine in a similarmanner to Example 10 (a).

MS (ES) 462 (M+H)⁺.

¹H NMR (DMSO-D6) 1.39 (s, 9H), 1.46-1.62 (m, 2H), 1.87-2.00 (m, 2H),3.08-3.25 (m, 2H), 3.61-3.73 (m, 2H), 5.10-5.23 (m, 1H), 6.84 (d, 1H),6.94 (bs, 2H), 7.29 (bs, 1H), 7.60 (bs, 1H), 7.60 (s, 1H), 7.80 (dd,1H), 8.25 (d, 1H), 10.96 (s, 1H).

b) 2-[1-(t-Butyloxycarbonyl)-piperidin-4-yloxy]-5-bromopyridine

Prepared from 2,5-dibromopyridine and 1-t-butyloxycarbonylpiperidin-4-olby the method of Example 10 (b).

MS (CI) 357 (M+H)⁺.

¹H NMR (DMSO-D6) 1.48 (s, 9H), 1.62-1.78 (m, 2H), 1.89-2.02 (m, 2H),3.20-3.34 (m, 2H), 3.68-3.83 (m, 2H), 5.10-5.21 (m, 1H), 6.62 (d, 1H),7.63 (dd, 1H), 8.14 (d, 1H).

Example 202-[(Aminocarbonyl)amino]-5-{3-[6-(piperidin-4-yloxy)]-pyridine}-3-thiophenecarboxamide

2-[(Aminocarbonyl)amino]-5-{3-[6-(1-t-butyloxycarbonyl-piperidin-4-yloxy)-pyridine}-3-thiophenecarboxamide(65 mg) was stirred in dichloromethane (3 ml). Trifluoroacetic acid (3ml) was added and stirring continued at room temperature for 1.5 h.Volatile materials were removed in vacuo, the residue was re-dissolvedin dichloromethane and the solution added to saturated aqueous sodiumhydrogen carbonate (3 ml). The dichloromethane was removed in vacuo andthe solid product collected by filtration, washed with water and dried(28 mg).

MS (ES) 362 (M+H)⁺.

¹H NMR (DMSO-D6) 1.42-1.58 (m, 2H), 1.87-2.00 (m, 2H), 2.51-2.69 (m,2H), 2.90-3.03 (m, 2H), 4.95-5.10 (m, 1H), 6.81 (d, 1H), 6.92 (bs, 2H),7.28 (bs, 1H), 7.57 (bs, 1H), 7.57 (s, 1H), 7.77 (dd, 1H), 8.23 (d, 1H).

Example 212-[(Aminocarbonyl)amino]-5-{3-[6-(1-(2-methoxyethyl)-piperidin-4-yloxy)]-pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(1-methoxyethylpiperidin-4-yloxy)-pyridine in a similar mannerto Example 10 (a).

MS (ES) 420 (M+H)⁺.

¹H NMR (DMSO-D6) 1.57-1.74 (m, 2H), 1.95-2.01 (m, 2H), 2.23-2.40 (m,2H), 2.40-2.60 (m, 2H), 2.64-2.85 (m, 2H), 3.22 (s, 3H), 3.43 (t, 2H),4.92-5.05 (bs, 1H), 6.81 (d, 1H), 6.93 (bs, 2H), 7.28 (bs, 1H), 7.60(bs, 1H), 7.60 (s, 1H), 7.77 (dd, 1H), 8.24 (d, 1H), 10.95 (s, 1H).

b) 5-Bromo-2-(1-methoxyethylpiperidin-4-yloxy)-pyridine

5-Bromo-2-(piperidin-4-yloxy)pyridine trifluoroacetate (0.86 g) wasstirred with potassium carbonate (0.838 g) in dimethylacetamide (5 ml).Bromoethyl methyl ether (0.342 ml) was added and the mixture was heatedat 80° C. for 20 minutes. After cooling the mixture was poured intowater (30 ml) and extracted three times with ether. The combinedextracts were washed with water, dried over magnesium sulfate, filteredand evaporated. The residue was purified by column chromatographyeluting with 0 to 2% 2M methanolic ammonia in dichloromethane to givethe product as a colourless oil (0.71 g).

MS (ES) 315 (M+H)⁺.

¹H NMR (DMSO-D6) 1.74-1.90 (m, 2H), 1.96-2.10 (m, 2H), 2.28-2.43 (m,2H), 2.60 (t, 2H), 2.73-2.86 (m, 2H), 3.36 (s, 3H), 3.52 (t, 2H),4.94-5.06 (m, 1H), 6.62 (d, 1H), 7.60 (dd, 1H), 8.14 (d, 1H).

c) 5-Bromo-2-(piperidin-4-yloxy)pyridine trifluoroacetate

2-[1-(t-Butyloxycarbonyl)-piperidin-4-yloxy]-5-bromopyridine was stirredin dichloromethane (8 ml). Trifluoroacetic acid (5 ml) was added andstirring continued at room temperature for 1.5 h. Volatile materialswere removed in vacuo and the residue was triturated with ether andhexane, then collected by filtration to give the product as a whitesolid (0.86 g).

MS (ES) 257 (M+H)⁺.

¹H NMR (DMSO-D6) 2.06-2.32 (m, 4H), 3.12-3.27 (m, 2H), 3.27-3.47 (m,2H), 5.25-5.38 (m, 1H), 6.68 (d, 1H), 7.69 (dd, 1H), 8.16 (dd, 1H), 9.42(bs, 1H), 9.57 (bs, 1H).

Example 222[(Aminocarbonyl)amino]-5-{3-[6-(N-methanesulphonyl)-piperidin-4-yloxy]-pyridine}-3-thiophenecarboxamide

2-[(N-Methanesulphonyl)piperidinyl-4-oxy]-5-bromopyridine (0.335 g) wasdissolved in tetrahydrofuran (10 ml) and cooled to −78° C. Triisopropylborate (0.46 ml) was added followed by dropwise addition of n-butyllithium (1.0 ml, 1.6 M solution in hexane). The reaction mixture wasallowed to warm to room temperature and stirred for 1 h The solvent wasthen evaporated off and the residue dissolved in a mixture of1,2-dimethoxyethane (8 ml) and water (1 ml) and purged with a stream ofargon. 2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (0.137 g)was then added followed by sodium carbonate (30 mg) and Pd(PPh₃)₄ (100mg). The mixture was heated at 90° C. under argon for 6 h. The reactionwas cooled, filtered and evaporated to dryness. The residue waspartitioned between 3N aqueous sodium carbonate and dichloromethane andthe solid interlayer was filtered off. The crude product was washed withwater and then with a 10% methanol in dichloromethane mixture. The solidwas chromatographed on silica using 10% methanol in dichloromethane aseluent to give the required product (20 mg).

MS (ES) 440 (M+H)⁺.

¹H NMR (DMSO-D6) 1.8 (m, 2H), 2.0 (m, 2H), 2.9 (s, 3H), 3.1 (m, 2H), 3.4(m, 2H), 5.15 (m, 1H), 6.8 (d, 1H), 6.95 (m, 2H), 7.2 (m, 1H), 7.6 (s,1H), 7.65 (m; 1H), 7.8 (d, 1H), 8.2 (s, 1H), 10.96 (m, 1H).

The preparation of the starting material was achieved as follows:

a) 2-(Piperidinyl-4-oxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and 4-hydroxypiperidine by the methodof Example 10 (b).

¹H NMR (CDCl₃) 1.6 (m, 2H), 2.1 (m, 2H), 2.8 (m, 2H), 3.2 (m, 2H), 5.0(m, 1H), 6.6 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H).

b) 2-[(N-methanesulphonyl)piperidinyl-4-oxy]-5-bromopyridine

A solution of 2-(piperidinyl-4-oxy)-5-bromopyridine (4.4 g) andtriethylamine (7.2 ml) in dichloromethane (150 ml) was cooled in an icebath under argon and a solution of mesyl chloride (1.9 ml) indichloromethane (50 ml) was added dropwise with stirring. After theaddition was complete the solution was stirred for a further 18 h atroom temperature. The mixture was diluted with more dichloromethane andwashed with water then brine and dried (sodium sulphate). The solventwas evaporated off and the residue washed with isohexane and the solidproduct was filtered off (3.8 g).

MS (ES) 335 (M+H)⁺.

¹H NMR (DMSO-D6) 1.7 (m, 2H), 2.0 (m, 2H), 2.9 (s, 3H), 3.1 (m, 2H),3.35 (m, 2H), 5.1 (m, 1H), 6.8 (m, 1H), 7.9 (m, 1H), 8.3 (m, 1H).

Example 232-[(Aminocarbonyl)amino]-5-{3-[6-(4,4-difluoropiperidin-1-yl)pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-(4,4-difluoro-piperidin-1-yl)pyridine in a similar manner toExample 9 (e).

MS (ES) 346 (M+H)⁺.

¹H NMR (DMSO-D6) 1.44-1.66 (m, 6H), 3.44-3.58 (m, 4H), 6.84 (d, 1H),6.90 (bs, 2H), 7.24 (bs, 1H), 7.47 (s, 1H), 7.56 (bs, 1H), 7.60 (dd,1H), 8.23 (d, 1H), 10.92 (s, 1H).

b) 5-Bromo-2-(4,4-difluoro-piperidin-1-yl)pyridine

2,5-Dibromopyridine (1.30 g) was heated with 4,4-difluoropiperidine (2g) in diaethylacetamide (4 ml) at 120° C. for 24 h, then at 150° C. for8 h. The solution was allowed to cool, then poured into water (30 ml).The aqueous phase was extracted with ether (×3) and the combinedextracts washed with water, dried over magnesium sulfate, filtered andevaporated. Purification by column chromatography gave the product as, acolourless oil (0.70 g).

MS (ES) 277 (M+H)⁺.

¹H NMR (DMSO-D6) 1.85-2.10 (m, 4H), 3.63-3.75 (m, 4H), 6.60 (d, 1H),7.55 (dd, 1H), 8.18 (d, 1H).

Example 242-[(Aminocarbonyl)amino]-5-{3-[6-(pyrrolidin-1-yl)-5-methyl]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from5-iodo-3-methyl-2-(pyrrolidin-1-yl)-pyridine in a similar manner toExample 9 (e).

MS (ES) 346 (M+H)⁺.

¹H NMR (DMSO-D6) 1.76-1.92 (m, 4H), 2.31 (s, 3H), 3.40-3.52 (m, 4H),6.89 (bs, 2H), 7.25 (bs, 1H), 7.43 (d, 1H), 7.47 (s, 1H), 7.58 (bs, 1H),8.07 (d, 1H), 10.92 (s, 1H).

b) 5-Iodo-3-methyl-2-(pyrrolidin-1-yl)-pyridine

Prepared from 2-bromo-5-iodo-3-methylpyridine (J. Org. Chem. 1995, 60(10), 5358) in a similar manner to Example 9 (d).

MS (ES) 289 (M+H)⁺.

¹H NMR (DMSO-D6) 1.85-1.97 (m, 4H), 2.27 (s, 3H), 3.44-3.56 (m, 4H),7.48 (d, 1H), 8.15 (d, 1H).

Example 252-[(Aminocarbonyl)amino]-5-{3-[6-(thien-2-ylmethoxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(thien-2-ylmethoxy)-5-bromopyridine by the method of Example 22.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 5.5 (s, 2H), 6.95 (m, 4H), 7.2 (s, 1H), 7.25 (m, 1H),7.5 (m, 1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.3 (s, 1H), 10.96 (brs, 1H).

b) 2-(Thien-2-ylmethoxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and thiophen-2-methanol by the methodof Example 10 (b).

¹H NMR (DMSO-D6) 5.5 (s, 2H), 6.65 (m, 1H), 7.0 (m, 1H), 7.1 (m, 1H),7.3 (m, 1H), 7.6 (m, 1H), 8.2 (m, 1H).

Example 262-[(Aminocarbonyl)amino]-5-{3-[6-(cyclopentylmethyl)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-cyclopentylmethoxy-5-bromopyridine by the method of Example 22.

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 1.3 (m, 2H), 1.6 (m, 4H), 1.8 (m, 2H), 2.3 (m, 1H), 4.1(d, 2H), 6.8 (d, 1H), 6.95 (m, 2H), 7.3 (brs, 1H), 7.6 (m, 2H), 7.8 (m,1H), 8.25 (m, 1H), 10.96 (brs, 1H).

b) 2-Cyclopentylmethoxy-5-bromopyridine

Prepared from 2,5-dibromopyridine and cyclopentylmethanol by the methodof Example 10 (b).

MS (ES) 256 (M+H)⁺.

Example 272-[(Aminocarbonyl)amino]-5-[3-(6-benzyloxy)pyridine]-3-thiophenecarboxamide

a) The title compound was prepared from 2-benzyloxy-5-bromopyridine bythe method of Example 22.

MS (ES) 369 (M+H)⁺.

¹H NMR (DMSO-D6) 5.4 (s, 2H), 6.9 (d, 1H), 6.95 (m, 2H), 7.35 (m, 4H),7.4 (m, 2H), 7.6 (m, 2H), 7.8 (m, 1H), 8.3 (m, 1H), 10.96 (brs, 1H).

b) 2-Benzyloxy-5-bromopyridine

Prepared from 2,5-dibromopyridine and benzyl alcohol by the method ofExample 10 (b).

MS (ES) 264 (M+H)⁺.

Example 282-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(tetrahydrofuran-3-yloxy)-5-bromopyridine by the method of Example 22.

MS (ES) 349 (M+H)⁺.

¹H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (m, 1H), 3.8 (m, 4H), 5.5 (m, 1H), 6.8(m, 1H), 6.95 (brs, 2H), 7.3 (m, 1H), 6 (m, 2H), 7.8 (m, 1H), 8.25 (s,1H), 10.96 (br, 1H).

b) 2-(Tetrahydrofuran-3-yloxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and 3-hydroxytetrahydrofuran by themethod of Example 10 (b).

¹H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (I, 1H), 3.8 (m, 4H), 5.4 (m, 1H), 6.8(d, 1H), 7.8 (m, 1H), 8.2 (m, 1H).

Example 292-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-ylmethoxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(tetrahydrofuran-3-ylmethoxy)-5-bromopyridine by the method of Example22.

MS (ES) 363 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6 (m, 1H), 2.0 (m, 1H), 2.6 (m, 1H), 3.5 (m, 1H), 3.6(m, 1H), 3.8 (m, 2H), 4.2 (m, 2H), 6.8 (d, 1H), 6.95 (m, 2H), 7.3 (brs,1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.25 (m, 1H), 10.96 (brs, 1H).

b) 2-(Tetrahydrofuran-3-ylmethoxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and tetrahydrofuran-3-methanol by themethod of Example 10 (b).

¹H NMR (DMSO-D6) 1.6 (m, 1H), 2.0 (m, 1H), 2.6 (m, 1H), 3.5 (m, 1H), 3.6(m, 1H), 3.7 (m, 2H), 4.2 (m, 2H), 6.8 (d, 1H), 7.8 (m, 1H), 8.2 (s,1H).

Example 302-[(Aminocarbonyl)amino]-5-{3-[6-(cyclopropylmethoxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-cyclopropylmethoxy-5-bromopyridine by the method of Example 22.

MS (ES) 333 (M+H)⁺.

¹H NMR (DMSO-D6) 0.25 (m, 2H), 0.35 (m, 2H), 1.25 (m, 1H), 4.05 (d, 2H),6.85 (d, 1H), 6.9 (m, 2H), 7.25 (m, 1H), 7.6 (m, 2H), 7.75 (m, 1H), 8.25(m, 1H), 10.93 (brs, 1H).

b) 2-(Cyclopropylmethoxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and cyclopropylmethanol by the methodof Example 10(b).

¹H NMR (DMSO-D6) 0.2 (m, 2H), 0.4 (m, 2H), 1.2 (m, 1H), 4.0 (d, 2H), 6.8(d, 1H), 7.8 (m, 1H), 8.2 (d, 1H).

Example 31(S)-2-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydrofuran-3-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from(S)-2-(tetrahydrofuran-3-yloxy)-5-bromopyridine by the method of Example22.

MS (ES) 349 (M+H)⁺.

¹H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (m, 1H), 3.8 (m, 4H), 5.5 (m, 1H), 6.8(d, 1H), 6.95 (m, 2H), 7.3 (brs, 1H), 7.6 (m, 2H), 7.8 (m, 1H); 8.25 (m,1H), 10.96 (brs, 1H).

b) (S)-2-(Tetrahydrofuran-3-yloxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and S-3-hydroxytetrahydrofuran by themethod of Example 10 (b).

¹H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (m, 1H), 3.8 (m, 4H), 5.4 (m, 1H), 6.8(d, 1H), 7.8 (m, 1H), 8.2 (d, 1H).

Example 322-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydropyran-4-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(tetrahydropyran-4-yloxy)-5-bromopyridine by the method of Example 22.

MS (ES) 363 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6 (m, 2H), 2.0 (m, 2H), 3.5 (m, 2H), 3.8 (m, 2H), 5.2(m, 1H), 6.8 (m, 1H), 6.95 (brs, 2H), 7.3 (m, 1H), 7.6 (m, 2H), 7.8 (m,1H), 8.2 (d, 1H), 10.96 (brs, 1H).

b) 2-(Tetrahydropyran-4-yloxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and tetrahydropyran-4-ol by the methodof Example 10 (b).

MS (ES) 258 (M+H)⁺.

Example 332-[(Aminocarbonyl)amino]-5-{3-[6-(tetrahydrothiopyran-3-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(tetrahydrothiopyran-3-yloxy)-5-bromopyridine by the method of Example22.

MS (ES) 379 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6 (m, 1H), 1.8 (m, 1H), 2.05 (m, 2H), 2.6 (m, 3H),2.9 (m, 1H), 5.1 (m, 1H), 6.8 (m, 1H), 6.9 (brs, 2H), 7.3 (m, 1H), 7.6(m, 2H), 7.8 (m, 1H), 8.25 (d, 1H), 10.96 (brs, 1H).

b) 2-(Tetrahydrothiopyran-3-yloxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and tetrahyrothiopyran-3-ol by themethod of Example 10 (b).

¹H NMR (DMSO-D6) 1.5 (m, 1H), 1.8 (m, 2H), 2.1 (m, 2H), 2.45 (m, 1H),2.6 (m, 1H), 2.8 (m, 1H), 5.0 (m, 1H), 6.8 (d, 1H), 7.8 (m, 1H), 8.2 (d,1H).

Example 342-[(Aminocarbonyl)amino]-5-{3-[6-(1-isopropylazetidin-3-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(1-isopropylazetidin-3-ol)-5-bromopyridine by the method of Example22.

MS (ES) 376 (M+H)⁺.

¹H NMR (DMSO-D6) 0.85 (d, 6H), 2.3 (m, 1H), 2.9 (m, 2H), 3.6 (m, 2H),5.05 (m, 1H), 6.8 (m, 1H), 6.9 (brs, 2H), 7.3 (m, 1H), 7.6 (m, 2H), 7.8(m, 1H), 8.2 (d, 1H), 10.96 (brs, 1H).

b) 2-(1-Isopropylazetidin-3-ol)-5-bromopyridine

Prepared from 2,5-dibromopyridine and 1-isopropylazetidin-3-ol (J.Heterocycl. Chem. 1987, 24, 255-259) by the method of Example 10 (b).

¹H NMR (DMSO-D6) 0.8 (d, 6H), 2.25 (m, 1H), 2.9 (m, 2H), 3.6 (m, 2H),5.0 (m, 1H), 6.8 (d, 1H), 7.9 (m, 1H), 8.2 (d, 1H).

Example 352-[(Aminocarbonyl)amino]-5-{3-[6-(benzyloxy-2-ethoxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(benzyloxy-2-ethoxy)-5-bromopyridine by the method of Example 22.

MS (ES) 413 (M+H)⁺.

¹H NMR (DMSO-D6) 3.75 (m, 2H), 4.4 (m, 2H), 4.55 (s, 2H), 6.85 (m, 1H),6.9 (m, 2H), 7.3 (m, 1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.25 (m, 1H), 10.96(brs, 1H).

b) 2-(Benzyloxyethoxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and benzyloxy-2-ethanol by the methodof Example 10 (b).

MS (ES) 308 (M+H)⁺.

Example 362-[(Aminocarbonyl)amino]-5-{3-[6-(N-methylpiperidin-3-yloxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(N-methylpiperidin-3-yloxy)-5-bromopyridine by the method of Example22.

MS (ES) 376 (M+H)⁺.

¹H NMR (DMSO-D6) 1.4 (m, 1H), 1.5 (m, 1H), 1.7 (m, 1H), 2.0 (m, 3H),2.15 (s, 3H), 2.8 (m, 2H), 5.0 (m, 1H), 6.8 (d, 1H), 6.95 (m, 2H), 7.3(m, 1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.25 (m, 1H), 10.96 (brs, 1H).

b) 2-(N-Methyl-piperidin-3-yloxy)-5-bromopyridine

Prepared from 2,5-dibromopyridine and N-methylpiperidin-3-ol by themethod of Example 10 (b).

¹H NMR (DMSO-D6) 1.4 (m, 1H), 1.5 (m, 1H), 1.7 (m, 1H), 1.9 (m, 1H), 2.0(m, 3H), 2.15 (m, 3H), 2.8 (m, 1H), 4.95 (m, 1H), 6.8 (d, 1H), 7.8 (m,1H), 8.2 (d, 1H).

Example 372-[(Aminocarbonyl)amino]-5-{3-[6-(2-(1-pyrrolidin-2-one)ethoxy)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from2-(2-(1-pyrrolidin-2-one)ethoxy)-5-bromopyridine by the method ofExample 22.

MS (ES) 390 (M+H)⁺.

¹H NMR (DMSO-D6) 0.8 (m, 2H), 1.9 (m, 2H), 2.2 (m, 2H), 3.55 (m, 2H),4.4 (m, 2H), 6.8 (m, 1H), 6.99 (m, 2H), 7.3 (m, 1H), 7.6 (m, 2H), 7.8(m, 1H), 8.3 (m, 1H), 10.96 (m, 1H).

b) 2-(2-(1-pyrrolidin-2-one)ethoxy)-5-bromo-pyridine

Prepared by the method of Example 10 (b) using 2,5-dibromopyridine and1-(2-hydroxyethyl)pyrrolidin-2-one.

MS (ES) 285 (M+H)⁺.

¹H NMR (DMSO-D6) 2.0 (q, 2H), 2.37 (t, 2H), 3.5 (t, 2H), 3.67 (t, 2H),4.43 (t, 2H), 4.43 (t, 2H), 6.65 (d, 1H), 7.64 (q, 1H), 8.16 (d, 1H).

Example 382-[(Aminocarbonyl)amino]-5-[3-(6-(morpholin-4-yl))pyridine]-3-thiophenecarboxamide

a) A mixture of 5-iodo-2-morpholinopyridine (1.26 g),bis(pinacolato)diboron (1.16 g), potassium acetate (1.28 g) andPdCl₂(dppf) (40 mg) in dimethylacetamide (15 ml) was flushed with argonwas heated at 80° C. for 4 h, and then allowed to cool.2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (0.287 g) wasadded, followed by a further portion of PdCl₂ (dppf) and 2M aqueoussodium hydrogen carbonate (8 ml). The mixture was heated at 90 C for 18h, then allowed to cool to room temperature and stirred for a further 48h. The solvent was removed in vacuo and the residue taken up in 2Maqueous sodium hydroxide (30 ml) and dichloromethane (30 ml). The layerswere separated and the organic phase was washed with a further portionof 2M aqueous sodium hydroxide (20 ml). The combined aqueous layers werethen washed with further dichloromethane (30 ml). The aqueous phase wasfiltered to remove a small amount of insoluble material and the filtratethen neutralised with 6M hydrochloric acid. The precipitated product wasthen collected by filtration and washed with water. The crude productwas triturated with a mixture of methanol and ether, filtered and driedto give the product as a brown solid (112 mg).

MS (ES) 348 (M+H)⁺.

¹H NMR (DMSO-D6) 400 MHz 3.40-3.60 (m, 4H), 3.60-3.80 (m, 4H), 6.54 (bs,2H), 6.85 (d, 1H), 7.09 (bs, 2H), 7.46 (s, 1H), 7.67 (dd, 1H), 8.32 (d,1H), 10.86 (s, 1H).

b) 4-(5-Iodo-pyridin-2-yl)morpholine

Prepared from 2-chloro-5-iodopyridine and morpholine by the method ofExample 9 (d).

MS (ES) 291 (M+H)⁺.

¹H NMR (DMSO-D6) 3.34-3.45 (m, 4H), 3.61-3.72 (m, 4H), 6.72 (d, 1H),7.77 (dd, 1H), 8.22 (d, 1H).

Example 392-[(Aminocarbonyl)amino]-5-{3-[6-(4-methylpiperazin-1-yl)]pyridine}-3-thiophenecarboxamide

a) The title compound was prepared from1-(5-bromo-pyridin-2-yl)-4-methylpiperazine in a similar manner toExample 38.

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 400 MHz 2.10-2.40 (s, 3H), 2.40-2.65 (m, 4H), 3.44-3.80(m, 4H), 6.56 (bs, 2H), 6.84 (d, 1H), 7.12 (bs, 2H), 7.47 (s, 1H), 7.66(d, 1H), 8.30 (s, 1H), 10.85 (s, 1H).

b) 1-(5-Bromo-pyridin-2-yl)-4-methylpiperazine

Prepared from 2,5-dibromopyridine and 4-methylpiperazine in a similarmanner to Example 9(d).

MS (ES) 256 (M+H)⁺.

¹H NMR (DMSO-D6) 2.18 (s, 3H), 2.30-2.40 (m, 4H), 3.36-3.50 (m, 4H),6.79 (d, 1H), 7.64 (dd, 1H), 8.13 (d, 1H).

Example 402-[(Aminocarbonyl)amino]-5-(4-[1,3,4-oxadiazol-2-yl]-2-phenyl)-3-thiophenecarboxamide

A solution of 2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide(0.26 g), sodium carbonate (0.23 g), and 4-[1,3,4-oxadiazol-2-yl]phenylboronic acid (0.38 g) in 1,2-dimethoxyethane (10 ml) and water (1 ml)was purged with argon for 10 minutes.Tetrakis(triphenylphosphine)palladium (0.2 g) was then added and themixture refluxed with stirring for 8 h. After cooling, the mixture wasfiltered and the resulting solid was washed with 2N sodium hydroxidesolution, then with water, and finally methanol, to give the requiredproduct (0.1 g).

MS (CI) 330 (M+H)⁺.

¹H NMR (DMSO-D6) 7.0 (m, 2H), 7.35 (m, 1H), 7.7 (m, 3H), 7.9 (s, 1H),8.0 (m, 2H), 9.3 (s, 1H), 11.04 (m, 1H).

4-[1,3,4-Oxadiazol-2-yl]phenyl boronic acid was prepared as described inGer. Offen. DE 19857765.

Example 412-[(Aminocarbonyl)amino]-5-(4-cyclopropylmethoxyphenyl)-3-thiophenecarboxamide

The title compound was prepared in a similar manner to Example 40 butusing 4-(cyclopropylymethoxy)-phenyl boronic acid.

MS (ES) 332 (M+H)⁺.

¹H NMR (DMSO-D6) 0.3 (m, 2H), 0.6 (m, 2H), 1.25 (m, 1H), 3.9 (d, 2H),6.9 (m, 2H), 6.95 (d, 1H), 7.25 (m, 1H), 7.4 (d, 1H), 7.65 (m, 1H),10.94 (brs, 1H).

Example 422-[(Aminocarbonyl)amino]-5-[3-(1,3-thiazol-4-ylmethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-[(3-bromophenoxy)methyl]-1,3-thiazole in a similar manner to Example 9(e) except that the crude solid obtained was purified by preparativeHPLC to give a brown solid (15 mg).

LCMS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6), 5.27 (s, 2H), 6.92 (m, 3H), 7.10 (m, 1H), 7.20 (s,1H), 7.30 (m, 2H), 7.64 (bs, 1H), 7.80 (m, 2H), 9.14 (s, 1H), 11.00 (s,1H).

b) 4-[(3-Bromophenoxy)methyl]-1,3-thiazole

4-(Chloromethyl)thiazole hydrochloride (3.0 g), 3-bromophenol (2.77 g)and potassium carbonate (7.30 g) were heated in dimethylformamide at 60°C., with stirring, for 18 h. The mixture was partitioned between diethylether (50 ml) and water (50 ml) and the aqueous phase was extractedfurther with ether (50 ml). The combined organics were washed with 2Maqueous sodium hydroxide (100 ml) and water (100 ml), dried (magnesiumsulphate) and concentrated in vacuo to give the product as a yellowcrystalline solid (3.82 g).

MS (ES) 270/272 (M+H)⁺.

¹H NMR (DMSO-D6) 5.21 (s, 2H), 7.02 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H),7.78 (s, 1H), 9.10 (s, 1H).

Example 432-[(Aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from N-(4-bromobenzyl)morpholine in asimilar manner to Example 9 (e) except that the compound was isolated byneutralisation of the basic aqueous phase followed by filtration,washing with water and drying of resulting precipitate to give a creamsolid (97 mg).

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 2.32 (t, 4H) 3.40 (s, 2H), 3.55 (t, 4H), 6.90 (bs, 2H),7.25 (m, 3H), 7.45 (d, 2H), 7.62 (bs, 1H), 7.65 (s, 1H), 10.97 (s, 1H).

b) N-(4-Bromobenzyl)morpholine

4-Bromobenzyl bromide (2.0 g) and morpholine (1.39 ml) were stirred indimethylformamide (25 ml) for 18 h. The mixture was partitioned betweendiethyl ether (50 ml) and water (80 ml). The aqueous phase was extractedfurther with ether (50 ml) and the combined organics were washed withwater (80 ml), dried (magnesium sulphate) and evaporated. The residuewas purified by column chromatography, eluting with a gradient of ethylacetate/iso-hexane; 0/100 to 50/50, to give the product as a whitecrystalline solid (1.44 g).

MS (ES) 256/258 (M+H)⁺.

¹H NMR (DMSO-D6) 2.30 (t, 4H), 3.40 (s, 2H), 3.55 (t, 4H), 7.22 (d, 2H),7.48 (d, 2H).

Example 442-[(Aminocarbonyl)amino]-5-(5-[2-(N-morpholinyl)]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from2-N-morpholino)-5-bromopyrimidine by the method of Example 9 (e).

MS (ES) 349 (M+H)⁺.

¹H NMR (DMSO-D6) 3.7 (m, 8H), 6.95 (br, 2H), 7.3 (br, 1H), 7.55 (s, 1H),7.6 (br, 1H), 8.5 (s, 2H), 10.94 (brs, 1H).

b) 2-(N-Morpholino)-5-bromopyrimidine

A solution of 2-chloro-5-bromopyrimidine (1.0 g) and morpholine (1.12ml) in dimethoxyacetamide (8 ml) was heated and stirred at 150° C. for 6h. After cooling, the reaction mixture was added to water and the solidwas filtered off and washed with water. The solid was dissolved in ethylacetate, washed with brine and the solvent phase was dried (magnesiumsulphate). On evaporation a solid was obtained (1.2 g).

MS (ES) 244/246 (M+H)⁺.

Example 452-[(Aminocarbonyl)amino]-5-(5-[2-(N-piperidinyl)]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from2-(N-piperidinyl)-5-bromopyrimidine by the method of Example 9 (e).

MS (ES) 347 (M+H)⁺.

¹H NMR (DMSO-D6) 1.5 (m, 4H), 1.6 (m, 2H), 3.7 (m, 4H), 7.3 (m, 1H),7.55 (s, 1H), 7.6 (m, 3H), 8.45 (s, 2H), 10.95 (brs, 1H).

b) 2-(N-Piperidinyl)-5-bromopyrimidine

Prepared from 2-chloro-5-bromopyrimidine and piperidine by the method ofExample 44 (b).

MS (ES) 242/244 (M+H)⁺.

Example 462-[(Aminocarbonyl)amino]-5-(5-[2-(N-pyrrolidinyl)]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from2-(N-pyrrolidinyl)-5-bromopyrimidine by the method of Example 9 (e).

MS (ES) 333 (M+H)⁺.

¹H NMR (DMSO-D6) 1.9 (m, 4H), 3.5 (m, 4H), 6.9 (m, 2H), 7.3 (m, 1H),7.45 (s, 1H), 7.6 (m, 1H), 8.45 (s, 2H), 10.94 (brs, 1H).

b) 2-(N-Pyrrolidinyl-5-bromopyrimidine

Prepared from 2-chloro-5-bromopyrimidine and pyrrolidine by the methodof Example 44 (b).

MS (ES) 228/230 (M+H)⁺.

Example 472-[(Aminocarbonyl)amino]-5-(5-[2-{4-(t-butyloxycarbonyl)piperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[4-(t-butyloxycarbonyl)piperazin-1-yl]pyrimidine by the methodof Example 9 (e).

MS (ES) 448 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.41 (s, 9H), 3.40 (t, 4H), 3.73 (t, 4H),6.93 (s, 2H), 7.29 (s, 1H), 7.54 (s, 1H), 7.59 (s, 1H), 8.50 (s, 2H),10.95 (s, 1H).

b) 5-Bromo-2-[4-(t-butyloxycarbonyl)piperazin-1-yl]pyrimidine

Prepared from 1-t-butoxycarbonylpiperazine by the method of Example 44(b).

MS (ES) 343, 345 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.40 (s, 9H), 3.37 (m, 4H), 3.67 (m, 4H),8.45 (s, 2H).

Example 482-[(Aminocarbonyl)amino]-5-(-5-[2-{4H-piperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide

A mixture of2-[(aminocarbonyl)amino]-5-(5-[2-{4-(t-butyloxycarbonyl)piperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide(120 mg), triethylsilane (1 ml) and dichloromethane (2 ml) was treatedwith trifluoroacetic acid (2 ml) and stirred at ambient temperature for1 h. After evaporation to dryness, trituration of the resultant oil withether gave a solid. This was dissolved in water, filtered and the pHadjusted to 7 to give the product (56 mg) as a yellow solid.

MS (ES) 348 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.72 (t, 4H), 3.66 (t, 4H), 6.92 (s, 2H),7.27 (s, 1H), 7.51 (s, 1H), 7.58 (s, 1H), 8.47 (s, 2H), 10.94 (s, 1H).

Example 492-[(Aminocarbonyl)amino]-5-(5-[2-{4-methylpiperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[4-methylpiperazin-1-yl]pyrimidine by the method of Example 10(a).

MS (ES) 362 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.21 (s, 3H), 2.38 (t, 4H), 3.72 (t, 4H),6.92 (s, 2H), 7.28 (s, 1H), 7.54 (s, 1H), 7.59 (s, 1H), 8.48 (s, 2H),10.95 (s, 1H).

b) 5-Bromo-2-[4-methylpiperazin-1-yl]pyrimidine

Prepared from 1-methylpiperazine by the method of Example 44 (b).

MS (ES) 257, 259 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.18 (3H, s), 2.32 (4H, t), 3.67 (4H, t),8.42 (2H, s).

Example 502-[(Aminocarbonyl)amino]-5-(5-[2-(3-dimethylaminopyrrolidin-1-yl)]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[3-dimethylaminopyrrolidin-1-yl]pyrimidine by the method ofExample 10 (a).

MS (ES) 376 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.15 (1H, m), 2.33 (1H, m), 2.67 (6H, s),3.47 (1H, m), 3.60 (1H, m), 3.76 (2H, m), 3.94 (1H, m), 6.93 (2H, s),7.29 (1H, s), 7.56 (1H, s), 7.62 (1H, s), 8.51 (2H, s), 10.95 (1H, s).

b) 5-Bromo-2-[3-dimethylaminopyrrolidin-1-yl]pyrimidine

Prepared from 3-dimethylaminopyrrolidine by the method of Example 44(b).

MS (ES) 271, 273 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.77 (1H, m), 2.10 (1H, m), 2.16 (6H, s),2.74 (1H, m), 3.13 (1H, m), 3.36 (1H, m) 3.62 (1H, m), 3.70 (1H, m),8.40 (2H, s).

Example 512-[(Aminocarbonyl)amino]-5-(5-[2-{2(S)-aminocarbonylpyrrolidin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-{2-(S)aminocarbonylpyrrolidin-1-yl}pyrimidine by the method ofExample 10 (a).

MS (ES) 376 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.93 (3H, m), 2.21 (1H, m), 3.54 (1H, m),3.67 (1H, m), 4.37 (1H, d), 6.84 (1H, s), 6.91 (2H, s), 7.29 (1H, s),7.32 (1H, s), 7.52 (1H, s), 7.61 (1H, s), 8.45 (2H, s), 10.94 (1H, s).

b) 5-Bromo-2-{2-(S)aminocarbonylpyrrolidin-1-yl}pyrimidine

Prepared from L-proline amide by the method of Example 44 (b).

MS (ES) 271, 273 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.91 (3H, m), 2.18 (1H, m), 3.48 (1H, m),3.59 (1H, m), 4.30 (1H, m), 6.84 (1H, s), 7.30 (1H, s), 8.41 (2H, s).

Example 522-[(Aminocarbonyl)amino]-5-(5-[2-{4-acetylpiperazin-1-yl}]pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-{4-acetylpiperazin-1-yl}pyrimidine by the method of Example 9(e).

MS (ES) 390 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.03 (3H, s), 3.51 (4H, t), 3.75 (4H, m),6.92 (2H, s), 7.28 (1H, s), 7.50 (1H, s), 7.54 (1H, s), 8.51 (2H, s),10.95 (1H, s).

b) 5-Bromo-2-{4-acetylpiperazin-1-yl}pyrimidine

Prepared from 1-acetylpiperazine by the method of Example 44 (b).

MS (ES) 285, 287 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.02 (3H, s), 3.50 (4H, dd), 3.69 (4H, m),8.46 (2H, s).

Example 532-[(Aminocarbonyl)amino]-5-(5-{2-[4,4-difluoropiperidin-yl]}pyrimidinyl)-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[4,4-difluoropiperidin-1-yl]pyrimidine by the method ofExample 9 (e).

MS (ES) 383 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.97 (4H, m), 3.85 (4H, t), 7.22 (1H, s),8.41 (2H, s).

b) 5-Bromo-2-[4,4-difluoropiperidin-1-yl]pyrimidine

Prepared from 4,4-difluoropiperidine by the method of Example 44 (b).

MS (ES) 278, 280 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 1.97 (4H, m), 3.84 (4H, t), 8.47 (2H, s).

Example 542-[(Aminocarbonyl)amino]-5-(5-{2-[3,3-difluoropyrrolidin-1-yl]}pyrimidinyl-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-[3,3-difluoropyrrolidin-1-yl]pyrimidine by the method ofExample 9 (e).

MS (ES) 369 (MH)⁺.

¹H NMR (DMSO-D6) 300 MHz δ 2.56 (2H, m), 3.74 (2H, t), 3.91 (2H, t),6.94 (2H, s), 7.29 (1H, s), 7.54 (1H, s), 7.59 (1H, s), 8.53 (2H, s),10.95 (1H, s).

b) 5-Bromo-2-[3,3-difluoropyrrolidin-1-yl]pyrimidine

Prepared from 3,3-difluoropyrrolidine by the method of Example 44 (b).

MS (ES) 264, 266 (MH)⁺.

¹H NMR (DMSO-D6) δ 2.52 (2H, m), 3.68 (2H, t), 3.85 (2H, t), 8.50 (2H,s).

Example 552-[(Aminocarbonyl)amino]-5-{2-(5-N-morpholinomethyl)thienyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-(5-bromothien-2-ylmethyl)morpholine in a similar manner to Example 9(e) except that further purification was achieved using columnchromatography eluting with methanol in dichloromethane mixtures.

MS (ES) 365 (M−H)⁻.

¹H NMR (DMSO-D6) 2.45 (m, 4H), 3.6 (m, 4H), 3.7 (s, 2H), 6.85 (d, 1H),6.9 (d, 1H), 6.95 (bs, 2H), 7.45 (s, 1H), 7.7 (bs, 1H), 11.0 (s, 1H).

b) 4-(5-Bromothien-2-ylmethyl)morpholine

Morpholine (0.96 g) was added portionwise to a solution of2-bromothiophene carboxaldehyde (1.195 g) in tetrahydrofuran (50 ml).After stirring at room temperature for 5 minutes, sodiumtriacetoxyborohydride (3.18 g) was added and the mixture stirred at roomtemperature for a further 3 h. The mixture was added to saturatedaqueous sodium bicarbonate (100 ml) and extracted twice with ethylacetate. The combined extracts were evapourated to dryness. The productwas purified by column chromatography elutinig with ethyl acetate inhexane mixtures to give a yellow oil (2.414 g).

MS (ES) 263 (M+H)⁺.

¹H NMR (DMSO-D6) 2.4 (t, 4H) 3.6 (t, 4H) 3.65 (s, 2H), 6.8 (d, 1H), 7.05(d, 1H).

Example 562-[(Aminocarbonyl)amino]-5-{2-benzyloxyphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from 2-bromophenylbenzyl ether in asimilar manner to Example 9 (e).

MS (ES) 366 (M−H)⁻.

¹H NMR (DMSO-D6) 5.3 (s, 2H), 6.85 (bs, 2H), 7.35-7.2 (m, 6H), 7.7-7.4(m, 5H), 7.75 (s, 1H), 11.0 (s, 1H).

b) 2-Bromophenybenzyl ether

Potassium carbonate (9.12 g) was suspended in dimethylformamide (25 ml)and 2-bromophenol (3.46 g) was added portionwise. Benzyl bromide (3.76g) was added and the mixture heated to 60° C. for 4 h. After cooling themixture was added to water (250 ml) and extracted three times withdiethyl ether. The organic layer was separated and washed with 2M sodiumhydroxide solution (100 ml) before drying over sodium sulphate. Afterfiltration, evaporation yielded (5.13 g) as a colourless oil.

MS (ES) 262 (M−H)⁻.

¹H NMR (DMSO-D6) 5.2 (s, 2H), 6.9 (td, 1H), 7.2 (dd, 1H), 7.32 (m, 1H),7.35 (m, 1H), 7.42 (m, 2H), 7.49 (m, 2H), 7.6 (dd, 1H).

Example 572-[(Aminocarbonyl)amino]-5-{2-(4-fluorophenylmethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from2-(4-fluorophenylmethoxy)bromobenzene in a similar manner to Example 9(e).

MS (ES) 384 (M−H)⁻.

¹H NMR (DMSO-D6) 5.25 (s, 2H), 6.85 (bs, 2H), 7.05 (t, 1H), 7.25-7.2 (m,4H), 7.7 (bs, 1H), 7.75-7.6 (m, 4H), 7.8 (s, 1H), 10.9 (s, 1H).

b) 2-(4-Fluorophenylmethoxy)bromobenzene

Prepared from 4-fluorobenzylbromide in a similar manner to Example 56(b).

MS (ES) 280 (M−H)⁻.

¹H NMR (DMSO-D6) 5.15 (s, 2H), 6.9 (td, 1H), 7.23 (m, 2H), 7.25 (m, 1H),7.35 (td, 1H), 7.54 (m, 1H), 7.6 (dd, 1H).

Example 582-[(Aminocarbonyl)amino]-5-{2-(2-[4-fluorophenyl]ethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from2-(2-[4-fluorophenyl]ethoxy)bromobenzene in a similar manner to Example9 (e):

MS (ES) 398 (M−H)⁻.

¹H NMR (DMSO-D6) 3.3 (t, 2H), 4.25 (t, 2H), 6.9 (bs, 2H), 7.0 (td, 1H),7.1 (m, 3H), 7.2 (m, 2H), 7.5 (m, 2H), 7.7 (m, 2H), 7.75 (s, 1H), 10.9(s, 1H).

b) 2-(2-[4-Fluorophenyl]ethoxy)bromobenzene

2-Bromophenol (3.46 g) was mixed with tetrahydrofuran (60 ml) andtriphenylphosphine (6.3 g) was added along with 4-fluorophenethylalcohol (4.2 g). The mixture was cooled in an ice bath before dropwiseaddition of diisopropyl azodicarboxylate (4.85 g). The mixture wasallowed to warm to room temperature over 18 h. The mixture wasevaporated and diethyl ether (100 ml) was added. Stirring was continuedfor 3 h, the mixture was filtered and the filtrate was evaporated. Theproduct was purified by column chromatography eluting with ethylacetate/hexane mixtures to give a yellow oil (4.47 g).

MS (ES) 294 (M−H)⁻.

¹H NMR (DMSO-D6) 3.05 (t, 2H), 4.2 (t, 2H), 6.9 (td, 1H), 7.1 (m, 3H),7.3 (td, 1H), 7.4 (m, 2H), 7.55 (dd, 1H).

Example 592-[(Aminocarbonyl)amino]-5-{2-(2-[4-chlorophenyl]ethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from2-(2-[4-chlorophenyl]ethoxy)bromobenzene in a similar manner to Example9 (e).

MS (ES) 414 (M−H)⁻.

¹H NMR (DMSO-D6) 3.2 (t, 2H), 4.25 (t, 2H), 6.85 (bs, 2H), 7.0 (td, 1H),7.1 (dd, 1H), 7.2 (m, 4H), 7.5 (d, 2H), 7.65 (m, 2H), 7.75 (s, 1H), 11.0(s, 1H).

b) 2-(2-[4-chlorophenyl]ethoxy)bromobenzene

Prepared from 4-chlorophenethyl alcohol in a similar manner to Example58 (b).

MS (ES) 310 (M−H)⁻.

¹H NMR (DMSO-D6) 3.05 (t, 2H), 4.3 (t, 2H), 6.85 (td, 1H), 7.45 (m, 5H),7.55 (dd, 1H).

Example 602-[(Aminocarbonyl)amino]-5-{2-(2-phenylethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from 2-(2-phenylethoxy)bromobenzenein a similar manner to Example 9 (e).

MS (ES) 380 (M−H)⁻.

¹H NMR (DMSO-D6) 3.2 (t, 2H), 4.3 (t, 2H), 6.8 (sb, 2H), 7.0 (td, 1H),7.1 (dd, 1H), 7.25 (m, 2H), 7.45-7.25 (m, 5H), 7.7 (m, 2H), 7.75 (s,1H), 11.0 (s, 1H).

b) 2-(2-Phenylethoxy)bromobenzene

Prepared from phenethyl alcohol in a similar manner to Example 58 (b).

MS (ES) 276 (M−H)⁻.

¹H NMR (DMSO-D6) 3.1 (t, 2H), 4.2 (t, 2H), 6.9 (td, 1H), 7.15 (dd, 1H),7.5-7.2 (m, 6H), 7.55 (dd, 1H).

Example 612-[(Aminocarbonyl)amino]-5-{4-chlorophenylmethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from2-(4-chlorophenylmethoxy)bromobenzene in a similar manner to Example 9(e).

MS (ES) 400 (M−H)⁻.

¹H NMR (DMSO-D6) 5.25 (s, 2H), 6.9 (bs, 2H), 7.0 (m, 1H), 7.1 (m, 1H),7.2 (m, 2H), 7.4 (d, 2H), 7.6 (d, 2H), 7.65 (m, 2H), 7.8 (s, 1H), 11.0(s, 1H).

b) 2-(4-Chlorophenylmethoxy)bromobenzene

Prepared from 4-chlorobenzyl bromide in a similar manner to Example 56(b).

MS (ES) 296 (M−H)⁻.

¹H NMR (DMSO-D6) 5.2 (s, 2H), 7.2 (dd, 1H), 7.35 (td, 1H), 7.5 (m, 4H),7.6 (dd, 1H).

Example 622-[(Aminocarbonyl)amino]-5-{2-[2-(N-morpholinyl)]ethylthio)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-[2-(2-bromophenylthio)ethyl]morpholine in a similar manner to Example9 (e).

MS (ES) 407 (M+H)⁺.

¹H NMR (DMSO-D6) 1.8 (m, 4H), 2.5 (partially obscured by DMSO), 3.0 (t,2H), 3.45 (m, 4H), 6.9 (bs, 2H), 7.2 (m, 2H), 7.35 (m, 2H), 7.4 (m, 2H),7.6 (bs, 1H), 11.0 (s, 1H).

b) 4-[2-(2-Bromophenylthio)ethyl]morpholine

Potassium carbonate (10.95 g) and 2-chloroethylmorpholine hydrochloride(5.9 g) were mixed with dimethylformamide (56 ml) and 2-bromothiophenolwas added before the mixture was heated to 100° C. for 3 days. Themixture was allowed to cool before water (500 ml) was added. The productwas extracted into diethyl ether (×3). The combined extracts were driedover sodium sulphate and filtered before evaporation. The product waspurified by column chromatography eluting with ethyl acetate/hexanemixtures to give a red/brown oil (6.024 g).

MS (ES) 303 (M+H)⁺.

¹H NMR (DMSO-D6) 2.5 (m, 4H), 2.7 (t 2H), 3.05 (t, 2H), 3.75 (m, 4H),7.05 (m, 1H), 7.25-7.2 (m, 2H), 7.7 (dd, 1H).

Example 632-[(Aminocarbonyl)amino]-5-{2-[2-(N-pyrrolidinyl)]ethylthio)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenylthio)ethyl]pyrrolidine in a similar manner to Example9 (e).

MS (ES) 391 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6 (m, 4H), 2.4 (m, 4H), 2.6 (t, 2H), 3.0 (t, 2H), 6.9(bs, 2H), 7.2 (m, 2H), 7.4-7.3 (m, 4H), 7.6 (bs, 1H), 11.0 (s, 1H).

b) 1-[2-(2-Bromophenylthio)ethyl]pyrrolidine

Prepared using 2-chloroethylpyrrolidine hydrochloride (5.36 g) in asimilar manner to Example 62 (b).

MS (ES) 287 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6 (m, 4H), 2.5 (partially obscured by DMSO), 2.7 (t,2H), 3.05 (t, 2H), 7.05 (m, 1H), 7.35 (m, 2H), 7.6 (dd, 1H).

Example 642-[(Aminocarbonyl)amino]-5-{2-[2-(N-piperidinyl)]ethylthio)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenylthio)ethyl]piperidine in a similar manner to Example9 (e).

MS (ES) 403 (M+H)⁺.

¹H NMR (DMSO-D6) 1.3 (m, 2H), 1.4 (m, 4H), 2.3 (m, 4H), 2.5 (partiallyobscured by DMSO), 3.0 (t, 2H), 7.0 (bs, 2H), 7.1 (bs, 1H), 7.5-7.2 (m,4H), 7.5 (s, 1H), 7.7 (bs, 1H), 11.0 (s, 1H).

b) 1-[2-(2-Bromophenylthio)ethyl]piperidine

Prepared using 2-chloroethylpiperidine hydrochloride (5.36 g) in asimilar manner to Example 62 (b).

MS (ES) 287 (M+H)⁺.

¹H NMR (DMSO-D6) 1.4 (m, 2H), 1.5 (m, 4H), 2.4 (m, 4H), 2.6 (t, 2H), 3.1(t, 2H), 7.1 (m, 1H), 7.4 (in, 2H), 7.6 (dd, 1H).

Example 652-[(Aminocarbonyl)amino]-5-[4-(pyrrolidinyl)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from 1-(4-iodophenyl)pyrrolidine in asimilar manner to Example 10 (a).

MS (ES) 330 (M)⁺.

¹H NMR (DMSO-D6, 300 MHz) 1.90-1.98 (m, 4H), 3.18-3.25 (m, 4H), 6.55 (d,2H), 6.83 (bs, 2H), 7.20 (bs, 1H), 7.35 (d, 2H), 7.40 (s, 1H), 7.60 (bs,1H), 10.89 (s, 1H).

b) 1-(4-Iodophenyl)pyrrolidine

Iodine (6.09 g) was added slowly to a stirred solution ofphenylpyrrolidine (3.21 g) and sodium bicarbonate (2.75 g) in water (30ml). The reaction was stirred for 1 h and then left to stand overnight.The solid was isolated by filtration, dissolved in ethanol (50 ml) anddiscoloured with aqueous sodium thiosulfate. The product was thenisolated by filtration and recrystalised from ethanol to give thedesired product as a brown/red powder (1.17 g).

MS (EI) 273 (M)⁺.

¹H NMR (DMSO-D6) 1.94 (t, 2H), 3.18 (t, 2H), 6.36 (d, 2H), 7.38 (d, 2H).

Example 662-[(Aminocarbonyl)amino]-5-[4-(piperidinyl)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from 1-(4-iodophenyl)piperidine in asimilar manner to Example 10 (a).

MS (ES) 345 (M+H)⁺.

¹H NMR (DMSO-D6) 300 MHz 1.50-1.65 (m, 6H), 3.15-3.25 (m, 4H), 6.80-6.95(m, 3H), 7.20 (bs, 1H), 7.35 (d, 2H), 7.50 (s, 1H), 7.65 (d, 2H), 10.91(s, 1H).

b) 1-(4-Iodophenyl)piperidine

Prepared from phenylpiperidine in a similar manner to Example 65 (b).

MS (ES) 288 (M+H)⁺.

¹H NMR (DMSO-D6) 300 MHz 1.45-1.65 (m, 6H), 3.05-3.15 (m, 4H), 6.75 (d,2H), 7.45 (d, 2H).

Example 672-[(Aminocarbonyl)amino]-5-[4-(N-imidazolyl)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from N-(bromophenyl)-1H-imidazole ina similar manner to Example 10 (a).

MS (ES) 328 (M+H)⁺.

¹H NMR (DMSO-D6) 300 MHz 6.95 (bs, 1H), 7.10 (s, 1H), 7.30 (bs, 1H),7.58-7.82 (m, 8H), 8.24 (s, 1h), 11.00 (s, 1H).

Example 682-[(Aminocarbonyl)amino]-5-[6-{(1-methylpyrrolidin-2-on-4-yl)methoxy}pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-{(1-methylpyrrolidin-2-on-4-yl)methoxy}pyridine in a similarmanner to Example 9 (e).

MS (ES) 390 (M+H)⁺ 388 (M−H)⁺.

¹H NMR (DMSO-D6) 11.10 (s, 1H), 8.30 (d, 1H), 7.85 (m, 1H), 7.60 (bs,1H), 7.40 (s, 1H), 7.30 (bs, 1H), 6.90 (d, 1H), 6.80-7.20 (bs, 2H),4.25-4.45 (m, 2H), 3.20-3.60 (m, 2H), 2.10-2.60 (m, 6H).

b) 5-Bromo-2-{(1-methylpyrrolidin-2-on-4-yl)methoxy}pyridine

Prepared from 2,5-dibromopyridine and4-hydroxymethyl-1-methylpyrrolidin-2-one by the method of Example 10(b).

MS (ES) 285.1 (M+H)⁺.

¹H NMR (CDCl₃) 8.16 (d, 1H), 7.64 (dd, 1H), 6.65 (d, 1H), 4.20-4.35 (m,2H), 3.52 (dd, 1H), 3.26 (dd, 1H), 2.85 (m, 1H), 2.86 (s, 3H), 2.59 (dd,1H), 2.31 (dd, 1H).

Example 692-[(Aminocarbonyl)amino]-5-{4-[2-(2-methoxyethoxy)ethoxy]-phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-bromo-[2-(2-methoxyethoxy)ethoxy]-benzene in a similar manner toExample 9 (e).

MS (ES) 380 (M+H)⁺.

¹H NMR (DMSO-D6) 10.93 (s, 1H), 7.60 (bs, 1H), 7.53 (s, 1H), 7.40 d,2H), 7.13 (bs, 1H), 6.93 (d, 2H), 6.40 (bs, 2H), 4.08 (m, 2H), 3.72 (m,2H), 3.56 (m, 2H), 3.46 (m, 2H), 3.30 (s, 3H), 3.25 (s, 3H).

b) 4-Bromo-[2-(2-methoxyethoxy)ethoxy]-benzene

Prepared by the method of M. Ouchi et al, J. Org. Chem., 52, 2420-7,1987 from 4-bromophenol and 2-(2-methoxyethoxy)ethyl tosylate.

MS (ES) 276 (M+H)⁺.

¹H NMR (CDCl₃) 7.35 (d, 2H), 67.79 (d, 2H), 4.10 (d, 2H), 3.84 (t, 2H),3.71 (t, 2H), 3.56 (t, 2H), 3.40 (s, 3H).

Example 702-[(Aminocarbonyl)amino]-5-{4-[2-(cyclopropylmethoxy)ethoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-(2-[cyclopropylmethoxy]ethoxy)-bromobenzene by the method of Example22 except that the crude solid was purified by preparative hplc.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 0.15 (m, 2H), 0.45 (m, 2H), 1.0 (m, 1H), 3.35 (m, 2H),3.7 (m, 2H) 4.1 (m, 2H), 6.9 (br, 2H), 6.95 (d, 2H), 7.25 (m, 1H), 7.4(d, 2H), 7.55 (s, 1H), 7.65 (m, 1H), 10.95 (brs, 1H).

b) 4-(2-[Cyclopropylmethoxy]ethoxy)-bromobenzene

Prepared by the method of Example 10 (b) using2-(4-bromophenoxyl)ethanol and cyclopropylmethyl bromide.

¹H NMR (DMSO-D6) 0.15 (m, 2H), 0.45 (m, 2H), 1.0 (m, 1H), 3.35 (m, 2H),3.75 (m, 2H), 4.1 (m, 2H), 6.95 (d, 2H), 7.45 (d, 2H).

Example 712-[(Aminocarbonyl)amino]-5-[6-(2,2-dimethyl-3-pyrrolidinylpropoxy)pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from2-(2,2-dimethyl-3-pyrrolidinylpropoxy)-5-bromopyridine by the method asExample 22 except that the crude solid was purified by preparative hplc.

MS (ES) 418 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (s, 6H), 1.65 (m, 4H), 3.3 (s, 2H), 3.5 (m, 4H),4.0 (s, 2H), 6.85 (d, 1H), 6.95 (br, 2H), 7.25 (br, 1H), 7.6 (br, 2H),7.8 (m, 1H), 8.25 (m, 1H), 10.95 (br, 1H).

b) 2-(2,2-Dimethyl-3-pyrrolidinylpropoxy)-5-bromopyridine

Prepared by the method of Example 10 (b) using 2,5-dibromopyridine and2,2-dimethyl-1-pyrrolidinylpropanol.

MS (ES) 314 (M+H)⁺.

Example 722-[(Aminocarbonyl)amino]-5-{3-chloro-4-(tetrahydrofuran-2-ylmethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-chloro-4-(tetrahydrofuran-2-ylmethoxy)-bromobenzene by the method ofExample 22.

MS (ES) 396 (M+H)⁺.

¹H NMR (DMSO-D6) 1.85 (m, 4H), 3.6-3.8 (m, 2H), 4.0 (m, 2H), 4.15 (m,1H), 6.9 (m, 2H), 7.15 (d, 1H), 7.2 (m, 1H), 7.35 (d, 1H), 7.5 (s, 1H),7.6 (m, 2H), 10.94 (brs, 1H).

b) 3-Chloro-4-(tetrahydrofuran-2-ylmethoxy)bromobenzene

Prepared by the method of Example 42 (b) using 2-chloro-4-bromophenoland tetrahydrofurfuryl bromide.

¹H NMR (DMSO-D6) 1.7-1.9 (m, 4H), 3.7 (m, 2H), 4.0 (m, 2H), 4.15 (m,1H), 7.1 (d, 1H), 7.4 (m, 1H), 7.6 (d, 1H).

Example 732-[(Aminocarbonyl)amino]-5-{4-(tetrahydrofuran-2-ylmethoxy)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-(tetrahydrofuran-2-ylmethoxy)-bromobenzene by the method of Example 22except that the crude solid was purified by preparative hplc.

MS (ES) 362 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65-2.0 (m, 4H), 3.7 (m, 2H), 3.95 (m, 2H), 4.15 (m,1H), 6.85 (m, 2H), 6.95 (d, 2H), 7.2 (m, 1H), 7.4 (d, 2H), 7.55 (s, 1H),7.6 (m, 1H), 10.92 (s, 1H).

b) 4-(Tetrahydrofuran-2-ylmethoxy)-bromobenzene

Prepared by the method of Example 42 (b) using 4-bromophenol andtetrahydrofurfuryl bromide.

MS (ES) 255 (M−H)⁻.

¹H NMR (DMSO-D6) 1.6-1.95 (m, 4H), 3.7 (m, 2H), 3.9 (m, 2H), 4.1 (m,1H), 6.9 (d, 2H), 7.4 (d, 2H).

Example 742-[(Aminocarbonyl)amino]-5-[(6-cyclopropylmethylthio)pyridin-3-yl]-3-thiophenecarboxamide

a) The title compound was prepared from5-bromo-2-cyclopropylmethylthio-pyridine in a similar manner to Example10.

MS (ES) 349 (M+H)⁺.

¹H NMR (DMSO-D6) 0.27-0.38 (m, 2H), 0.49-0.62 (m, 2H), 1.04-1.21 (m,1H), 3.12 (d, 2H), 7.00 (bs, 1H), 7.33 (d, 1H), 7.34 (bs, 1H), 7.69 (bs,1H), 7.75 (dd, 1H), 7.78 (s, 1H), 8.59 (d, 1H), 11.03 (s, 1H).

b) 5-Bromo-2-cyclopropylmethylthio-pyridine

Prepared from 2,5-dibromopyridine and cyclopropylmethane thiol by themethod of Example 10 (b).

MS (EI) 244 (M)⁺.

¹H NMR (DMSO-D6) 0.25-0.34 (m, 2H), 0.54-0.62 (m, 2H), 1.02-1.22 (m,1H), 3.09 (d, 2H), 7.07 (d, 1H), 7.56 (dd, 1H), 8.45 (d, 1H).

Example 752-[(Aminocarbonyl)amino]-5-{4-[2-(2-methoxyethoxy)ethoxy]-3-methylphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-bromo-[2-(2-methoxethoxy)ethoxy]-2-methylbenzene in a similar mannerto Example 9 (e).

MS (ES) 394 (M+H)⁺.

¹H NMR (DMSO-D6) 10.92 (s, 1H), 7.60 (bs, 1H), 7.52 (s, 1H), 7.21-7.30,(m, 2H), 7.21 (bs, 1H), 6.94 (d, 1H), 6.89 (bs, 2H), 4.10 (m, 2H), 3.72(m, 2H), 3.59 (m, 2H), 3.44 (m, 2H), 3.23 (s, 3H), 2.15 (s, 3H).

(b) 4-Bromo-[2-(2-methoxyethoxy)ethoxy]-2-methylbenzene

Prepared by the method of Example 42 (b) from 4-bromo-2-methylphenol and2-(2-methoxyethoxy)ethyl tosylate.

MS (EI) 288 (M⁺).

¹H NMR (CDCl₃) 7.10-7.18 (m, (2H), 6.68 (d, 1H), 4.09 (t, 2H), 3.87 (t,2H), 3.71 (m, 2H), 3.55 (t, 2H), 3.38 (s, 3H), 2.20 (s, 3H).

Example 762-[(Aminocarbonyl)amino]-5-{3-chloro-4-[2-(2-methoxyethoxy)ethoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-bromo-2-chloro-[2-(2-methoxyethoxy)ethoxy]benzene in a similar mannerto Example 9 (e).

MS (ES) 414 (M+H)⁺.

¹H NMR (DMSO-D6) 10.94 (s, 1H), 7.66 (s, 1H), 7.59 (bs, 1H), 7.52 (d,1H), 7.36, (m, 1H), 7.28 (bs, 1H), 7.16 (d, 1H), 6.93 (bs, 2H), 4.18 (m,2H), 3.76 (m, 2H), 3.60 (m, 2H), 3.44 (m, 2H), 3.23 (s, 3H).

b) 4-Bromo-2-chloro-[2-(2-methoxyethoxy)ethoxy]benzene

Prepared from 4-bromo-2-chlorophenol and 2-(2-methoxyethoxy)ethyltosylate by the method of Example 42 (b).

MS (EI) 310 (M⁺).

¹H NMR (CDCl₃) 7.49 (d, 1H), 7.24-7.32 (m, 2H), 6.81 (d, 1H), 4.17 (t,2H), 3.89 (t, 2H), 3.73 (t, 2H), 3.56 (t, 2H), 3.39 (s, 3H).

Example 772-[(Aminocarbonyl)amino]-5-[2-(4-methylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide

a) 2-[(Aminocarbonyl)amino]-5-[2-formylphenyl]-3-thiophenecarboxamide(0.1 g) and sodium tri-acetoxy borohydride (0.1 g) were mixed withtetrahydrofuran (10 ml). N-Methylpiperazine (0.04 g) was added and themixture stirred at room temperature for 18 h. Separation was achievedusing cation exchange chromatography eluting withammonia/methanol/dichloromethane mixtures. This gave the title compound(0.07 g).

MS (ES) 374 (M+H)⁺.

¹H NMR (DMSO-D6) 2.2 (s, 3H), 2.35 (m, 4H), 3.3 (m, 4H), 3.5 (s 2H), 6.8(bs, 2H), 7.2-7.5 (m, 6H), 7.7 (bs 1H), 11.0 (s, 1H).

(b) 2-[(Aminocarbonyl)amino]-5-[2-formylphenyl]-3-thiophenecarboxamide

Prepared from 2-formylphenyl boronic acid in a similar manner to Example9 (e).

MS (ES) 290 (M+H)⁺.

¹H NMR (DMSO-D6) 7.0 (bs, 2H), 7.35 (bs, 1H), 7.4 (s, 1H), 7.5 (td, 1H),7.6 (dd, 1H), 7.7 (td, 1H), 7.8 (bs, 1H), 7.9 (dd, 1H), 10.1 (s, 1H),11.1 (s, 1H).

Example 782-[(Aminocarbonyl)amino]-5-[2-(4-isopropylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide

The title compound was prepared from N-isopropylpiperazine in a similarmanner to Example 77 (a).

MS (ES) 401 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 2.3-2.4 (m, 8H), 3.5 (s 2H), 6.9 (bs, 2H),7.25-7.4 (m, 5H), 7.45 (m, 1H), 7.65 (bs 1H), 11.0 (s, 1H).

Example 792-[(Aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazinylmethyl)phenyl]-3-thiophenecarboxamide

The title compound was prepared from N-t-butyloxycarbonylpiperazine in asimilar manner to Example 77 (a).

MS (ES) 460 (M+H)⁺.

¹H NMR (DMSO-D6) 1.4 (d, 9H), 2.3 (m, 4H), 3.5 (s 2H), 6.9 (bs, 2H),7.2-7.5 (m, 6H), 7.65 (bs 1H), 11.0 (s, 1H).

Example 802-[(Aminocarbonyl)amino]-5-[4-(pyrrolidinylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from 1-(4-bromobenzyl)pyrrolidine ina similar manner to Example 10 (a).

LCMS (ES) 345 (M+H)⁺.

¹H NMR (DMSO-D6) 1.70 (s, 4H), 2.53 (s, 4H+DMSO), 3.62 (s, 2H), 6.90 (s,2H), 7.25 (m, 1H), 7.30 (d, 2H), 7.45 (d, 2H), 7.62 (m, 1H), 7.69 (s,1H), 10.97 (s, 1H).

b) 1-(4-Bromobenzyl)pyrrolidine

Prepared in a similar manner to Example 43 (b) but using pyrrolidine.

MS (ES) 240/242 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65 (m, 4H), 2.38 (m, 4H), 3.50 (s, 2H), 7.22 (m, 2H),7.45 (m, 2H).

Example 812-[(Aminocarbonyl)amino]-5-[2-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from4,4-difluoro-(2-(2-bromophenoxy)ethyl)piperidine in a similar manner toExample 9 (e).

MS (ES) 425 (M+H)⁺.

¹H NMR (DMSO-D6) 1.9 (m, 4H), 2.7 (m, 4H), 2.9 (t, 2H), 4.2 (t, 2H), 6.9(bs, 2H), 7.0 (t, 1H), 7.1 (d, 1H), 7.2 (m, 2H), 7.6 (m, 2H), 7.75 (s,1H), 11.0 (s, 1H).

b) 4,4-Difluoro-(2-(2-bromophenoxy)ethyl)piperidine

2-(2-Bromophenoxy)ethyl tosylate (1.86 g), 4,4-difluoropiperidine (0.73g) and potassium carbonate (0.97 g) were mixed with dimethylformamide(30 ml) and heated to 60° C. for 18 h. The mixture was cooled and addedto water (300 ml). The mixture was extracted with diethyl ether (×3),dried and evaporated. Purification was achieved using cation exchangechromatography eluting with ammonia/methanol/dichloromethane mixturesyielding 4-difluoro-(2-(2-bromophenoxy)ethyl)piperidine (0.77 g).

MS (ES) 321 (M+H)⁺.

¹H NMR (DMSO-D6) 1.8-2.1 (m, 4H), 2.7 (m, 4H), 2.8 (t, 2H), 4.1 (t, 2H),6.9 (td, 1H), 7.1 (dd, 1H), 7.3 (td, 1H), 7.55 (dd, 1H).

c) 2-(2-Bromophenoxy)ethyl tosylate

2-(2-Bromophenoxy)ethanol (17.4 g) was dissolved in dichloromethane (250ml) and cooled to 0° C. Triethylamine (9.7 g) was added along with tosylchloride (18.3 g). The mixture was stirred for 2 h, then added to water(500 ml). The organics were washed twice with 2N hydrochloric acid anddried. Separation was achieved using silica chromatography eluting withhexane/ethyl acetate mixtures. This gave 2-(2-bromophenoxy)ethyltosylate (14.4 g).

¹H NMR (DMSO-D6) 2.4 (s, 2H), 4.3 (t, 2H), 4.35 (t, 2H), 6.9 (td, 1H),7.0 (dd, 1H), 7.3 (td, 1H), 7.5 (d, 2H), 7.6 (dd, 1H), 7.8 (d, 2H).

d) 2-(2-Bromophenoxy)ethanol

Potassium carbonate (23.8 g) and 2-bromophenol (14.9 g) were mixed withdimethylformamide (150 ml). 2-Bromoethanol (12.9 g) was added and themixture heated to 50° C. for 18 h. The mixture was cooled and added towater (1500 ml). The product was extracted into diethyl ether (×3) andwashed twice with dilute sodium hydroxide solution Evaporation gave2-(2-bromophenoxy)ethanol (17.4 g).

¹H NMR (DMSO-D6) 3.75 (m, 2H), 4.0 (t, 2H), 4.9 (t, 1H), 6.8 (t, 1H),7.1 (d, 1H), 7.3 (d, 1H), 7.55 (d, 1H).

Example 822-[(Aminocarbonyl)amino]-5-[2-(2-(3,3-difluoropyrrolidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from3,3-difluoro-(2-(2-bromophenoxy)ethyl)pyrrolidine in a similar manner toExample 9 (e).

MS (ES) 411 (M+H)⁺.

¹H NMR (DMSO-D6) 2.2 (m, 2H), 2.9 (t, 2H), 3.0 (m, 4H), 4.2, (t, 2H),6.9 (bs, 2H), 7.0 (t, 1H), 7.15 (d, 1H), 7.2 (m, 2H), 7.6 (m, 2H), 7.8(s, 1H), 11.0 (s, 1H).

b) 3,3-Difluoro-(2-(2-bromophenoxy)ethyl)pyrrolidine

Prepared from 3,3-difluoropyrrolidine in a similar manner to Example 81(a).

MS (ES) 307 (M+H)⁺.

¹H NMR (DMSO-D6) 2.2 (m, 2H), 2.9 (m, 4H), 3.1 (t, 2H), 4.1, (t, 2H),6.9 (td, 1H), 7.1 (dd, 1H), 7.3 (td, 1H), 7.6 (dd, 1H).

Example 833-[(Aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide

a) The title compound was prepared from3-amino-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide in asimilar manner to Example 9(b).

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 2.35 (m, 4H), 3.5 (s, 2H), 3.55 (m, 4H), 6.55 (brs,2H), 7.4 (m, 3H), 7.55 (d, 2H), 8.2 (s, 1H), 10.03 (brs, 1H).

b) 3-[4-(Morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile

(i) To a solution of methyl 4-bromomethylbenzoate (14.75 g) indimethylformamide (50 ml), cooled to 5° C., was added rapidly morpholine(13.8 ml). The mixture was stirred at room temperature for 2 h. Themixture was partitioned between diethyl ether and water. The organiclayer was washed with water, dried (MgSO₄), evaporated and purified bycolumn chromatography eluting with ethyl acetate/iso-hexane (20:80) togive methyl 4-(morpholin-4-ylmethyl)benzoate (14.13 g) as an oil.

(ii) To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml),cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion inoil). The mixture was stirred for 30 minutes before the addition of asolution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) intetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for5 h. The mixture was cooled, quenched with saturated ammonium chloride(20 ml) and extracted with ethyl acetate. The organic extracts weredried (MgSO₄) and evaporated to give a gum which was purified by columnchromatography eluting with a 20-100% ethyl acetate/iso-hexane gradientto give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g).

MS (ES) 245 (M+H)⁺.

¹H NMR (CDCl₃) 2.45 (m, 4H), 3.55 (s, 2H), 3.7 (m, 4H), 4.05 (s, 2H),7.5 (d, 2H), 7.9 (d, 2H).

c)cis/trans-2-Cyano-1-[4-(morpholin-4-ylmethyl)phenyl]ethenyl-4-methylbenzenesulphonate

To a solution of 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile(0.96 g) in tetrahydrofuran (12 ml) was added sodium hydride (190 mg,60% dispersion in oil) and the resulting mixture was stirred at roomtemperature for 1 h. A solution of p-toluenesulphonyl chloride (0.9 g)in tetrahydrofuran (20 ml) was added and the resulting mixture wasstirred at room temperature for 3 h The reaction was quenched with waterand extracted with ethyl acetate. The organic extracts were dried(MgSO₄) and evaporated to give a gum, which was purified by columnchromatography eluting with ethyl acetate/isohexane (50:50) to give acis/trans mixture of 2-cyano-1-[4-(morpholin-4-ylmethyl)phenyl]ethenyl4-methylbenzenesulphonate (0.94 g) as an oil.

MS (ES) 399 (M+H)⁺.

d)cis/trans-2-({2-Cyano-1-[4-(morpholinylmethyl)-phenyl]ethenyl}thio)acetamide

To a solution of the above cis/trans mixture of2-cyano-1-[4-(morpholin-4-ylmethyl)phenyl]ethenyl4-methylbenzenesulphonate (940 mg) in acetonitrile (20 ml) was addedfreshly prepared thioacetamide (430 mg) followed by triethylamine (0.75ml). The resulting mixture was stirred at room temperature for 18 h.Further amounts of thioacetamide (660 mg) and triethylamine (1.5 ml)were added and the resulting mixture was stirred for a further 3 h. Themixture was evaporated and the resulting gum was purified by columnchromatography eluting with a 1-8% methanol/dichioromethane gradient togive a cis/trans mixture of2-({2-cyano-1-[4-(morpholin-4-ylmethyl)phenyl]ethenyl}thio)acetamide(712 mg) as a gum.

MS (ES) 318 (M+H)⁺.

e) 3-Amino-5-[4-(morpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide

To a suspension ofcis/trans-2-({2-cyano-1-[4-(morpholin-4-ylmethyl)phenyl]ethenyl}thio)acetamide(705 mg) in tetrahydrofuran (15 ml) was added potassium t-butoxide (250mg) and the resulting mixture was stirred at room temperature for 18 h.The mixture was poured into 50% brine and extracted with ethyl acetate.The organic layer was dried (MgSO₄) and evaporated to give a gum, whichwas purified by column chromatography eluting with a 1-8%methanol/dichloromethane gradient to give3-amino-5-[4-(morpholin-4-ylmethyl)phenyl]-thiophene-2-carboxamide (161mg).

MS (ES) 318 (M+H)⁺.

¹H NMR (DMSO-D6) 2.35 (m, 4H), 3.5 (s, 2H), 3.6 (m, 4H), 6.45 (s, 2H),6.85 (s, 2H), 6.9 (s, 1H), 7.35 (d, 2H), 7.5 (d, 2H).

Example 843-[(Aminocarbonyl)amino]-5-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene-2-carboxamide

a) The title compound was prepared from3-amino-5-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene-2-carboxamidein a similar manner to Example 9 (b).

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.65 (t, 2H), 2.7 (d, 2H), 3.45 (s, 2H),3.75 (m, 2H), 6.6 (brs, 2H), 7.35 (d+s, 4H), 7.55 (d, 2H), 8.2 (s, 1H),10.03 (brs, 1H).

b)3-Amino-5-[4-(cis-2,6-dimethylmorpholin-4-yl-methyl)-phenyl]thiophene-2-carboxamide

Prepared in a similar manner to Example 83 (b-e) using cis2,6-dimethylmorpholine.

MS (ES) 346 (M+H)⁺.

¹H NMR (DMSO-D6) 1.1 (d, 6H), 1.8 (t, 2H), 2.7 (d, 2H), 3.5 (s, 2H), 3.7(m, 2H), 5.2 (s, 2H), 5.7 (s, 2H), 6.8 (s, 1H), 7.35 (d, 2H), 7.5 (d,2H).

Example 852-[(Aminocarbonyl)amino]-6-[4-(cis-2,6-dimethylmorpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared fromN-(4-bromobenzyl)-cis-2,6-dimethylmorpholine in a similar manner toExample 10 (a).

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.65 (t, 2H), 2.7 (m, 2H), 3.4 (s, 2H),3.55 (m, 2H), 7.0 (brs, 2H), 7.3 (m, 3H), 7.5 (d, 2H), 7.7 (s, 1H), 7.7(brs, 1H), 11.0 (s, 1H).

b) N-(4-Bromobenzyl)-cis-2,6-dimethylmorpholine

The compound was prepared in a similar manner to Example 43 (b).

MS (ES) 284, 286 (M+H)⁺.

¹H NMR (CDCl₃) 1.15 (d, 6H), 1.7 (t, 2H), 2.65 (d, 2H), 3.4 (s, 2H), 3.7(m, 2H), 7.2 (d, 2H), 7.45 (d, 2H).

Example 862-[(Aminocarbonyl)amino]-5-[(6-{4-morpholino}methyl)pyridin-3-yl]thiophene-3-carboxamide

a) The title compound was prepared from5-bromo-2-[(4-morpholino)methyl]pyridine in a similar manner to Example9(e).

MS (ES) 362 (M+H)⁺.

¹H NMR (DMSO-D6) 2.4 (m, 4H), 3.6 (s, 2H), 3.6 (m, 4H), 7.0 (brs, 2H),7.3 (brs, 1H), 7.45 (d, 1H), 7.7 (brs, 1H), 7.8 (s, 1H), 7.85 (dd, 1H),8.65 (d, 1H), 11.0 (brs, 1H),

b) 5-Bromo-2-[(4-morpholino)methyl]pyridine

To a solution of 5-bromopyridine-2-carboxaldehyde (0.88 g) in anhydrousdichloroethane (20 ml) was added morpholine (0.48 ml), followed byglacial acetic acid (0.29 ml) and sodium triacetoxyborohydride (1.49 g).The resulting mixture was stirred at room temperature for 2 h. Themixture was quenched with saturated sodium bicarbonate (20 ml) andstirred for 30 minutes. The mixture was extracted with ethyl acetate,dried (MgSO₄) and evaporated to give a gum, which was purified by columnchromatography eluting with ethyl acetate/iso-hexane (1:1) to give acolourless oil (1.035 g).

MS (ES) 257, 259 (M+H)⁺.

¹H NMR (CDCl₃) 2.5 (m, 4H), 3.6 (s, 2H), 3.7 (m, 4H), 7.35 (d, 1H), 7.75(dd, 1H), 8.6 (d, 1H).

Example 872-[(Aminocarbonyl)amino]-5-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from3-(4-bromobenzyl)-8-oxa-3-azabicyclo[3.2.1]octane in a similar manner toExample 9(e).

MS (ES) 387 (M+H)⁺.

¹H NMR (DMSO-D6) 1.7 (m, 2H), 1.85 (m, 2H), 2.15 (m, 2H), 3.3-3.45 (m,4H), 4.15 (d, 2H), 6.95 (brs, 2H), 7.3 (d, 2H), 7.3 (brs, 1H), 7.5 (d,2H), 7.7 (brs+s, 2H), 10.95 (brs, 1H).

b) 3-(4-Bromobenzyl)-8-oxa-3-azabicyclo[3.2.1]octane

This compound was prepared in a similar manner to example 43(b) butusing 8-oxa-3-azabicyclo[3.2.1]octane.

MS (ES) 282 (M+H)⁺.

¹H NMR (CDCl₃) 1.9 (m, 2H), 1.95 (m, 2H), 2.3 (d, 2H), 2.5 (d, 2H), 3.4(s, 2H), 4.3 (m, 2H), 7.2 (d, 2H), 7.4 (d, 2H).

Example 882-[(Aminocarbonyl)amino]-5-[3-(morpholin-4-ylmethyl-4-isobutylphenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-(5-bromo-2-isobutoxybenzyl)morpholine in a similar manner to Example9(e).

MS (ES) 433 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 2.05 (m, 1H), 2.4 (m, 4H), 3.5 (s, 2H),3.55 (m, 4H), 3.75 (d, 2H), 6.9 (brs, 2H), 7.0 (d, 1H), 7.2 (brs, 1H),7.35 (dd, 1H), 7.45 (d, 1H), 7.55 (s, 1H), 7.7 (brs, 1H), 10.9 (brs,1H).

b) 4-(5-Bromo-2-isobutoxybenzyl)morpholine

To a solution of 5-bromo-2-isobutoxybenzaldehyde (2.46 g) in1,2-dichloroethane (40 ml) was added morpholine (0.96 ml) and aceticacid (0.57 ml). The mixture was stirred for 30 minutes before theaddition of sodium triacetoxyborohydride (3.04 g). The resulting mixturewas stirred at room temperature for 3 h. The reaction was quenched withsaturated sodium bicarbonate (30 ml) and stirred for 30 minutes beforeextraction with ethyl acetate. The organic extracts were dried (MgSO₄)and evaporated to give an oil, which was purified by columnchromatography eluting with ethyl acetate/iso-hexane (20:80) to give4-(5-bromo-2-isobutoxybenzyl)morpholine (2.88 g) as an oil.

MS (ES) 328 (M+H)⁺.

¹H NMR (CDCl₃) 1.05 (d, 6H), 2.1 (m, 1H), 2.5 (m, 4H), 3.5 (s, 2H), 3.7(m, 6H), 6.7 (d, 1H), 7.3 (m, 1H), 7.5 (m, 1H).

c) 5-Bromo-2-isobutoxybenzaldehyde

To a solution of 5-bromo-2-hydroxybenzaldehyde (7.63 g) indimethylformamide (40 ml) was added anhydrous potassium carbonate (15.7g) followed by 1-bromo-2-methylpropane (6.2 ml). The resulting mixturewas heated to 70° C. for 18 h. The mixture was partitioned between waterand ethyl acetate. The organic layer was washed with 2N sodiumhydroxide, dried (MgSO₄) and evaporated to give an oil which waspurified by column chromatography eluting with ethyl acetate/iso-hexane(10:90) to give 5-bromo-2-isobutoxybenzaldehyde (9.52 g) as an oil.

MS (ES) 256 (M+H)⁺.

¹H NMR (CDCl₃) 1.1 (d, 6H), 2.2 (m, 1H), 3.85 (d, 2H), 6.9 (d, 1H), 7.6(dd, 1H), 7.9 (d, 1H), 10.45 (brs, 1H).

Example 892-[(Aminocarbonyl)amino]-5-[3-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide

The title compound was prepared from N-(3-bromobenzyl)morpholine in asimilar manner to Example 43 except that the product was adsorbed on toreverse phase silica and eluted with water/acetonitrile/trifluoroaceticacid to give a cream solid (120 mg).

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 2.37 (brs, 4H), 3.47 (s, 2H), 3.59 (brs, 4H), 6.99(brs, 2H), 7.17 (d, 1H), 7.34 (t+brs, 2H), 7.42 (d, 1H), 7.47 (s, 1H),7.74 (s, 2H), 11.02 (s, 1H).

Example 902-[(Aminocarbonyl)amino]-5-(4-{[2-(methoxymethyl)morpholin-4-yl]methyl}phenyl)thiophene-3-carboxamide

The title compound was prepared from4-(4-bromobenzyl)-2-(methoxymethyl)morpholine (0.7 g) in a similarmanner to Example 43 to give the product as a light brown solid (28 mg).

MS (ES) 405 (M+H)⁺.

¹H NMR (DMSO-D6) 1.80 (t, 1H), 2.04 (m, 1H), 2.64 (m, 2H), 3.19 (s, 3H),3.20-3.40 (m, 2H), 3.40-3.57 (m, 4H), 3.74 (d, 1H), 6.92 (brs, 2H), 7.26(brs, 1H), 7.29 (d, 2H), 7.47 (d.2H), 7.68 (brs, 1H), 7.70 (s, 1H),10.97 (s, 1H).

4-(4-Bromobenzyl)-2-(methoxymethyl)morpholine

2-(Methoxymethyl)morpholine (1 g), anhydrous potassium carbonate (2.1g), 1-bromo-4-(bromomethyl)benzene (1.91 g) and dimethylformamide (30ml) were stirred at ambient temperature for 48 h, evaporated, and theresidue purified by column chromatography using a gradient ofether/isohexane; 0/100 to 100/0, 1/9 MeOH/dichloromethane and finally 2Mammonia in methanol to give the product as a solid (0.7 g).

MS (ES) 300 (M+H)⁺.

¹H NMR (CDCl₃) 1.89 (t, 1H), 2.11 (m, 1H), 2.58 (m, 2H), 3.28 (s, 3H),3.30 (m, 2H), 3.37 (s, 2H), 3.60 (m, 2H), 3.81 (m, 1H), 7.12 (d, 2H),7.36 (d, 2H).

Example 912-[(Aminocarbonyl)amino]-5-[3-fluoro-4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide

a) 4-(4-Bromo-2-fluorobenzyl)morpholine (1.2 g) was stirred intetrahydrofuran (25 ml) under argon and the mixture cooled to −70° C.n-Butyl lithium (4.1 ml, 1.6M solution in hexane) was added dropwiseover 20 minutes and the mixture was stirred for a further 30 minutes at−70° C. Triisopropylborate (1.52 ml) was then added in one portion andthe reaction mixture was allowed to warm to room temperature over 2 h,then concentrated in vacuo. 1,2-Dimethoxyethane (45 ml) was added to theresidue and the mixture was purged with a stream of argon.2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (0.385 g) wasthen added, followed by saturated aqueous sodium hydrogen carbonate (5ml) and Pd(PPh₃)₄ (100 mg). The mixture was stirred at 85° C. underargon for 18 h. After cooling, the solvent was removed in vacuo and theresidue was partitioned between 2M aqueous sodium hydroxide (50 ml) anddichloromethane (50 ml). The aqueous layer was extracted further withdichloromethane (50 ml) and the compound was isolated by neutralisationof the basic aqueous phase, followed by filtration, washing with waterand drying of the resulting precipitate to give the product as a brownsolid (370 rag).

MS (ES) 379 (M+H)⁺.

¹H NMR (DMSO-D6) 2.38 (t, 4H) 3.50 (s, 2H), 3.55 (t, 4H), 6.95 (brs,2H), 7.25 (s, 1H), 7.30 (d, 2H), 7.39 (t, 1H), 7.62 (brs, 1H), 7.79 (s,1H), 10.98 (brs, 1H).

b) 4-(4-Bromo-2-fluorobenzyl)morpholine

4-Bromo-2-fluorobenzyl bromide (3.0 g) and morpholine (2.15 ml) werestirred in dimethylformamide (30 ml) at ambient temperature for 18 h.The mixture was partitioned between diethyl ether (80 ml) and water (80ml). The aqueous phase was extracted further with diethyl ether (80 ml)and the combined organic phases were dried (magnesium sulfate) andconcentrated in vacuo. The residue was purified by columnchromatography, eluting with a gradient of 0-30% ethylacetate/iso-hexane to give the product as a colourless oil (2.92 g).

MS (ES) 274 (M+H)⁺.

¹H NMR (DMSO-D6) 2.35 (t, 4H), 3.48 (s, 2H), 3.55 (t, 4H), 7.38 (q, 2H),7.49 (d, 1H).

Example 922-[(Aminocarbonyl)amino]-5-[3-chloro-4-(morpholin-4-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-(4-bromo-2-chlorobenzyl)morpholine in a similar manner to Example 91(a) to give a brown solid (270 mg).

MS (ES) 395 (M+H)⁺.

¹H NMR (DMSO-D6) 2.40 (m, 4H) 3.51 (s, 2H), 3.57 (m, 4H), 6.97 (brs,2H), 7.30 (brs, 1H), 7.43 (d, 1H), 7.48 (d, 1H), 7.55 (s, 1H), 7.62(brs, 1H), 7.80 (s, 1H), 10.97 (s, 1H).

b) 4-(4-Bromo-2-chlorobenzyl)morpholine

The title compound was prepared from4-bromo-1-(bromomethyl)-2-chlorobenzene in a similar manner to Example91 (b) except that the residue was purified by column chromatography,eluting with a gradient of 0-20% ethyl acetate/iso-hexane to give theproduct as a colourless oil (1.20 g).

MS (ES) 290 (M+H)⁺.

¹H NMR (DMSO-D6) 2.40 (t, 4H), 3.50 (s, 2H), 3.57 (t, 4H), 7.42 (d, 1H),7.53 (d, 1H), 7.69 (s, 1H).

c) 4-Bromo-1-(bromomethyl)-2-chlorobenzene

4-Bromo-2-chlorotoluene (7.02 g) and N-bromosuccinimide (6.07 g) wasstirred in chlorobenzene (50 ml) under ultraviolet light at 100° C. for18 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by medium-pressureliquid chromatography, eluting with iso-hexane, to give a colourless oil(2.65 g).

MS (EI) 282 M⁺.

¹H NMR (DMSO-D6) 4.70 (s, 2H), 7.58 (s, 2H), 7.78 (s, 1H).

Example 932-[(Aminocarbonyl)amino]-5-{4-[(4,4-difluoropiperidin-1-yl)methyl]phenyl}thiophene-3-carboxamide

a) 4,4-Difluoro-1-(4-bromobenzyl)piperidine (0.81 g) was stirred intetrahydrofuran (20 ml) under argon, and the mixture cooled to −65° C.n-Butyl lithium (2.66 ml, 1.6M solution in hexane) was added dropwiseover 20 minutes and the mixture was stirred for a further 30 minutes at−65° C. Triisopropylborate (1.31 ml) was then added in one portion andthe reaction mixture was allowed to warm to room temperature over 2 h.,then concentrated in vacuo. 1,2-Dimethoxyethane (25 ml) was added to theresidue and mixture was purged with a stream of argon.2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (0.250 g) wasthen added followed by saturated aqueous sodium hydrogen carbonate (5ml) and Pd(PPh₃)₄ (100 mg). The mixture was stirred at 80° C. underargon for 18 h. After cooling, the solvent was removed in vacuo and theresidue was partitioned between 2M aqueous sodium hydroxide (15 ml) anddichloromethane (15 ml). The solid remaining undissolved at theinterface was collected by filtration, washed with water anddichloromethane and dried to give the product as a grey solid (0.243 g).

LCMS (ES) 395 (M+H)⁺.

¹H NMR (DMSO-D6) 1.90 (m, 4H), 2.50 (m, obscured), 3.50 (s, 2H), 6.90(s, 2H), 7.25 (m, 3H), 7.42 (d, 2H), 7.62 (s, 1H), 7.68 (s, 1H), 10.97(s, 1H).

b) 4,4-Difluoro-1-(4-bromobenzyl)piperidine

4-Bromobenzyl bromide (1.55 g) and 4,4-difluoropiperidine (1.50 g) werestirred in dimethylformamide (30 ml) for 18 h. The mixture waspartitioned between diethyl ether (40 ml) and water (40 ml). The aqueousphase was extracted further with ether (40 ml) and the combined organicphases were washed with water (50 ml), dried (MgSO₄) and concentrated invacuo to give the product as a white crystalline solid (1.57 g). 2

¹H NMR (DMSO-D6) 1.90 (m, 4H), 2.45 (m, 4H obscured), 3.48 (s, 2H), 7.22(d, 2H), 7.50 (d, 2H).

Example 942-[(Aminocarbonyl)amino]-5-[4-(1-{piperidin-1-yl}ethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from1-[1-(4-bromophenyl)ethyl]piperidine in a similar manner to Example 93(a) except that the compound was isolated by neutralisation of the basicaqueous phase with aqueous 6M HCl, followed by filtration, washing withwater and drying of the resulting precipitate to give a light brownsolid (307 mg).

MS (ES) 373 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 5H), 1.50 (m, 4H), 2.45 (m, obscured), 3.55(m, 1H), 6.60 (s, 2H), 7.12 (s, 2H), 7.30 (d, 2H), 7.45 (d, 2H), 7.60(s, 1H), 10.90 (s, 1H).

b) 1-[1-(4-Bromophenyl)ethyl]piperidine

4-Bromoacetophenone (1.95 g), piperidine (0.97 ml) and titanium(IV)isopropoxide (3.64 ml) were stirred under argon at room temperature for1 h. Ethanol (10 ml) was added, followed by sodium cyanoborohydride(0.41 g) and mixture stirred for 18 h. Water (2 ml) was then added andthe mixture stirred for 20 minutes. The resulting inorganic precipitatewas filtered off, washed with ethanol (20 ml) and the combined organicphase was concentrated in vacuo, redissolved in toluene and purified byBondelute® chromoatography, eluting with 0-20% ethyl acetate/iso-hexaneto give the product as a pale yellow oil (1.07 g).

MS (ES) 268 (M+H)⁺.

¹H NMR (DMSO-D6) 1.21 (d, 3H), 1.30 (m, 2H), 1.42 (m, 4H), 2.22 (m, 4H),3.40 (q, 1H), 7.20 (d, 2H), 7.45 (d, 2H).

Example 952-[(Aminocarbonyl)amino]-5-{4-[(1R)-1-morpholin-4-ylethyl]phenyl}thiophene-3-carboxamide

a) The title compound was prepared from4-[(1R)-1-(4-bromophenyl)ethyl]morpholine in a similar-manner to Example93 (a) except that the compound was isolated by neutralisation of thebasic aqueous phase with aqueous 6M HCl, followed by filtration, washingwith is water and drying of the resulting precipitate to give a palebrown solid (278 mg).

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.22 (d, 3H), 2.25 (m, 2H), 2.40 (m, 2H), 3.30 (m, 1H),3.50 (m, 4H), 6.90 (brs, 2H), 7.25 (m, 3H), 7.42 (d, 2H), 7.65 (m, 2H),10.97 (s, 1H).

b) (1R)-4-[1-(4-Bromophenyl)ethyl]morpholine

(R)-(+)-1-(4-Bromophenyl)ethylamine (0.98 g), 2,2′-dibromodiethyl ether(1.36 g) and diisopropylethylamine (2.5 ml) were stirred indimethylformamide (20 ml) under argon at 100° C. for 18 h. The reactionmixture was allowed to cool to room temperature, then partitionedbetween diethyl ether (50 ml) and water (50 ml). The aqueous phase wasextracted further with diethyl ether (50 ml) and the combined organicphases were washed with water (100 ml), dried (MgSO₄), concentrated invacuo, redissolved in toluene and purified by Bondelute® chromatography,eluting with 0-50% ethyl acetate/iso-hexane to give the product as ayellow oil (0.86 g).

LCMS (ES) 270 (M+H)⁺.

¹H NMR (DMSO-D6) 1.21 (d, 3H), 2.20 (m, 2H), 2.38 (m, 2H), 3.30 (m, 1H),3.50 (m, 4H), 7.22 (d, 2H), 7.48 (d, 2H).

Example 962-[(Aminocarbonyl)amino]-5-(4-{[4-(2-methoxyethyl)piperazin-1-yl]methyl}phenyl)thiophene-3-carboxamide

a) The title compound was prepared from1-(4-bromobenzyl)-4-(2-methoxyethyl)piperazine in a similar manner toExample 93 (a) except that the compound was isolated by neutralisationof the basic aqueous phase with aqueous 6M HCl, followed by filtration,washing with water and drying of the resulting precipitate to give alight brown solid (271 mg).

MS (ES) 418 (M+H)⁺.

¹H NMR (DMSO-D6) 2.25-2.50 (m, obscured), 3.20 (s, 3H), 3.40 (m, 4H),6.90 (brs, 2H), 7.22 (m, 31H), 7.42 (d, 2H), 7.60 (brs, 1H), 7.63 (s,1H), 10.96 (s, 1H).

b) 1-(4-Bromobenzyl)-4-(2-methoxyethyl)piperazine

4-Bromobenzyl bromide (2.0 g) and 1-(2-methoxyethyl)piperazine (2.31 g)were stirred in dimethylformamide (30 ml) for 18 h. The mixture waspartitioned between diethyl ether (30 ml) and water (30 ml). The aqueousphase was extracted further with ether (30 ml) and the combined organicswere washed with water (50 ml), dried (MgSO₄), concentrated in vacuo andpurified by Bondelute® chromatography, eluting with 0-100% ethylacetate/iso-hexane followed by 10-50% methanol/ethyl acetate to give theproduct as a yellow oil (1.61 g).

¹H NMR (DMSO-D6) 2.22-2.45 (m, 10H), 3.20 (s, 3H), 3.40 (m, 4H), 7.20(m, 2H), 7.45 (m, 2H).

Example 972-[(Aminocarbonyl)amino]-5-[4-(piperidin-1-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from 1-(4-bromobenzyl)piperidine in asimilar manner to Example 93 (a) except that the compound was isolatedby neutralisation of the basic aqueous phase with aqueous 6M HCl,followed by filtration, washing with water and drying of the resultingprecipitate to give a pale brown solid (182 mg).

LCMS (ES) 359 (M+H)⁺.

¹H NMR (DMSO-D6) 1.40 (m, 2H), 1.50 (m, 4H), 2.42 (m, 4H), 3.50 (brs,2H), 6.92 (m, 2H), 7.28 (m, 3H), 7.45 (m, 2H), 7.65 (m, 2H), 10.98 (brs,1H).

b) 1-(4-Bromobenzyl)piperidine

This compound was prepared from piperidine in a similar manner toExample 96 (b), giving the compound as a clear oil (1.22 g).

MS (ES) 254 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 2H), 1.45 (m, 4H), 2.22 (m, 4H), 3.38 (s, 2H),7.20 (m, 2H), 7.43 (m, 2H).

Example 982-[(Aminocarbonyl)amino]-5-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]phenyl}thiophene-3-carboxamide

a) The title compound was prepared from(1S,4S)-5-(4-bromobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane in a similarmanner to Example 93 (a), as a pale brown solid (180 mg).

LCMS (ES) 373 (M+H)⁺.

¹H NMR (DMSO-D6) 1.58 (m, 1H), 1.80 (m, 1H), 2.40 (d, 1H), 2.70 (m, 1H),3.40 (s, 1H), 3.50 (m, 1H), 3.65 (m, 2H), 3.90 (d, 1H), 4.32 (s, 1H),6.90 (brs, 2H), 7.22 (m, 1H), 7.30 (d, 2H), 7.42 (d, 2H), 7.62 (m, 2H),10.96 (brs, 1H).

b) (1S,4S)-5-(4-Bromobenzyl)-2-oxa-5-azabicyclo[2.2.1]heptane

(1S,4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane hydrochloride (1.26 g),4-bromobenzyl bromide (2.32 g) and triethylamine (3.88 ml) were stirredin dimethylformamide (30 ml) for 18 h. The mixture was partitionedbetween diethyl ether (60 ml) and water (60 ml) and the organic phasewas washed further with water (60 ml), dried (MgSO₄), concentrated invacuo and purified by Bondelute® chromatography, eluting with 0-100%ethyl acetate/iso-hexane to give the product as an orange oil (1.91 g).

MS (ES) 267 (M)⁺.

¹H NMR (DMSO-D6) 1.57 (m, 1H), 1.78 (m, 1H), 2.18 (m, 1H), 2.65 (m, 1H),3.40 (s, 1H), 3.50 (m, 1H), 3.62 (m, 2H), 3.90 (d, 1H), 4.30 (s, 1H),7.25 (d, 2H), 7.43 (d, 2H).

Example 995-{4-[(4-Acetylpiperazin-1-yl)methyl]phenyl}-2-[(aminocarbonyl)amino]thiophene-3-carboxamide

a) Bis-(pinacolato)diboron (1.23 g), potassium acetate (1.19 g) anddichloro[1,1′-bis-(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (59 mg) were added to a solution of1-acetyl-4-(4-bromobenzyl)piperazine (1.20 g) in dimethylacetamide (20ml) whilst purging with argon and the mixture stirred at 80° C. for 16h, then allowed to cool to ambient temperature and2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (213 mg),saturated aqueous sodium bicarbonate solution (5 ml) anddichloro[1,1′-bis-(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (59 mg) were added and the mixture was stirred at90° C. for 18 h. After cooling, the solvent was removed in vacuo and theresidue was partitioned between 2M aqueous sodium hydroxide (20 ml) anddichloromethane (20 ml). The aqueous phase was then extracted furtherwith dichloromethane (2×20 ml) and neutralised with aqueous 6M HCl. Theresulting precipitate was filtered and purified using cation exchangechromatography eluting with ammonia/methanol/dichloromethane mixtures.This gave the title compound as a brown solid (17 mg).

LCMS (ES) 402 (M+H)⁺.

¹H NMR (DMSO-D6) 1.95 (s, 3H), 2.30 (m, 4H), 3.40 (m, 4H), 3.45 (s, 2H),6.90 (brs, 2H), 7.25 (m, 3H), 7.42 (d, 2H), 7.62 (brs, 1H), 7.65 (s,1H), 10.97 (brs, 1H).

b) 1-Acetyl-4-(4-bromobenzyl)piperazine

This compound was prepared from 1-acetylpiperazine in a similar mannerto Example 96 (b), giving the compound as a yellow oil (1.23 g).

¹H NMR (DMSO-D6) 1.95 (s, 3H), 2.20-2.40 (m, 4H), 3.40 (m, 4H), 3.45 (s,2H), 7.22 (m, 2H), 7.50 (m, 2H).

Example 1002-[(Aminocarbonyl)amino]-5-[4-(1,4-oxazepan-4-ylmethyl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from 4-(4-bromobenzyl)-1,4-oxazepanein a similar manner to Example 93 (a) except that the compound wasisolated by neutralisation of the basic aqueous phase with aqueous 6MHCl, followed by filtration, washing with water and drying of theresulting precipitate to give a dark brown solid (341 mg).

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.80 (m, 2H), 2.60 (m, 4H), 3.58 (m, 4H), 3.65 (t, 2H),6.90 (brs, 2H), 7.25 (brs, 1H), 7.30 (d, 2H), 7.45 (d, 2H), 7.65 (m,2H), 10.97 (brs, 1H).

b) 4-(4-Bromobenzyl)-1,4-oxazepane

The compound was prepared from homomorpholine hydrochloride in a similarmanner to Example 98 (b) to give the product as a yellow oil (4.51 g).

¹H NMR (DMSO-D6) 1.75 (m, 2H), 2.60 (m, 4H), 3.55 (m, 4H), 3.65 (m, 2H),7.25 (d, 2H), 7.46 (d, 2H).

Example 101(1S)-2-((Aminocarbonyl)amino)-5-(4-(1-{morpholin-4-yl}ethyl)phenyl)thiophene-3-carboxamide

a) The compound was made from (1S)-4-(1-(4-bromophenyl)ethyl)morpholine(1.6 g) in a similar manner to Example 10 (a) except that thetriisopropyl borate was added after the butyl lithium solution in thefirst step; the solvent for the second step was dimethoxyethane/water(10:1) and solid sodium hydrogen carbonate was used and finalpurification was by preparative hplc to yield the product as a creamsolid (530 mg).

MS (ES) 373 (M−H)⁻.

¹H NMR (DMSO-D6) 1.27 (d, 3H), 2.21-2.3 (m, 2H), 2.33-2.44 (m, 2H),3.22-3.38 (m, 5H), 6.93 (brs, 2H), 7.21-7.32 (m, 3H), 7.46 (d, 2H),7.6-7.7 (m, 2H), 10.97 (brs, 1H).

b) (1S)-4-(1-(4-Bromophenyl)ethyl)morpholine

(1S)-(−)-1-(4-Bromophenyl)ethylamine (2.4 g), 2,2′-dibromodiethylether(3.25 g) and N,N-diisopropylethylamine (6 ml) were heated to 100° C. indimethylformamide (40 ml) for 18 h, allowed to cool and partitionedbetween water and ethyl acetate. The organic phase was dried (MgSO₄),evaporated under vacuum and purified by column chromatography using a0-40% ethyl acetate/iso-hexane gradient. The product was obtained as ayellow oil (1.91 g).

MS (ES) 270 (M+H)⁺.

¹H NMR (CDCl₃) 1.3 (d, 3H), 2.26-2.38 (m, 2H), 2.4-2.51 (m, 2H), 3.16(q, 1H), 3.59-3.6 (m, 4H), 7.19 (d, 2H), 7.42 (d, 2H).

Example 1022-((Aminocarbonyl)amino)-5-(4-(1-methyl-1-{morpholin-4-yl}ethyl)phenyl)thiophene-3-carboxamide

a) The compound was made from4-({1-(4-bromophenyl)-1-methyl}ethyl)morpholine (150 mg) in a similarmanner to Example 10(a) except that the triisopropyl borate was addedafter the butyl lithium solution in the first step, the solvent for thesecond step was dimethoxyethane/water (10:1) and solid sodium hydrogencarbonate was used and final purification was by preparative hplc toyield the product as a cream solid (6 mg).

MS (ES) 387 (M−H)⁻.

¹H NMR (DMSO-D6) 1.35 (s, 6H), 2.35-2.43 (m, 4H), 3.51-3.6 (m, 4H), 6.95(brs, 2H), 7.31 (brs, 1H), 7.45-7.55 (m, 4H), 7.65-7.55 (m, 2H), 11.01(s, 1H).

b) 4-({1-(4-Bromophenyl)-1-methyl}ethyl)morpholine

The compound was made in a similar manner to Example 101 (b) using1-(4-bromophenyl)-1-methylethylamine to yield the product as a yellowgum (150 mg).

MS (ES) 284 (M+H)⁺.

¹H NMR (CDCl₃) 1.3 (s, 6H), 2.36-2.47 (m, 4H), 3.57-3.69 (m, 4H),7.32-7.42 (m, 4H).

1-(4-Bromophenyl)-1-methylethylamine

The title compound was prepared according to J. Org. Chem., 1968,33(12), 4515.

Example 1032-[(Aminocarbonyl)amino]-5-[4-((4-methylpiperazin-1-yl)methyl)phenyl]thiophene-3-carboxamidea) 2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)thiophene-3-carboxamide

2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (11.75 g) wasstirred in 1,2-dimethoxyethane (500 ml) and saturated aqueous sodiumbicarbonate solution (100 ml), and 4-formylphenyl boronic acid (10 g)was added. The flask was flushed with argon, andtetrakis-(triphenylphosphine)palladium(0) (5.1 g) was then added. Thereaction was stirred at 90° C. for 2 h, then cooled and evaporated underreduced pressure. The residue was treated with dichloromethane (200 ml)and 2N sodium hydroxide solution (100 ml), and stirred for twentyminutes. The resulting solid was then isolated by filtration, andpurified by trituration with ethanol (100 ml), giving the product as apale green solid (5.75 g).

MS (ES) 290 (M+H)⁺.

¹H NMR (DMSO-D6) 7.05 (s, 2H), 7.40 (s, 1H), 7.75 (m, 3H), 7.90 (d, 2H),8.00 (s, 1H), 9.95 (s, 1H), 11.10 (s, 1H).

b)2-[(Aminocarbonyl)amino]-5-[4-((4-methylpiperazin-1-yl)methyl)phenyl)-thiophene-3-carboxamide

2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) andN,N-dimethylacetamide (5 ml). 1-Methyl piperazine (0.16 g) was added,followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). Thereaction was stirred at 80° C. for 20 minutes, and thenpolymer-supported cyanoborohydride (0.45 g) was added. The reaction wasstirred at 80° C. for a further 2 h, and then polymer-supportedisocyanate (0.5 g) was added. The resins were removed by filtration, andthe filtrate was then passed through a 5 g SCX column, washing withmethanol (25 ml). The product was eluted using 1M methanolic ammonia (45ml), and this solution was then evaporated to dryness under reducedpressure and the residue purified by chromatography on silica, elutingwith dichloromethane/methanol (9:1), to give the product as an off-whitesolid (16 mg).

MS (ES) 374 (M+H)⁺.

¹H NMR (DMSO-D6) 2.15 (m, 3H), 2.30 (m, 8H), 3.45 (s, 2H), 6.90 (s, 2H),7.30 (m, 3H), 7.50 (d, 2H), 7.65 (m, 2H), 10.95 (s, 1H).

Example 1042-[(Aminocarbonyl)amino]-5-[4-((2-ethoxycarbonylpiperidin-1-yl)methyl)phenyl]-thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 103 (b)but from 2-(ethoxycarbonyl)piperidine (CAS Registry No. 15862-72-3).

MS (ES) 431 (M+H)⁺.

¹H NMR (DMSO-D6) 1.20 (t, 3H), 1.30-1.55, (m, 4H), 1.70 (m, 2H), 2.15(m, 1H), 2.80 (m, 1H), 3.15 (m, 1H), 3.40 (d, 1H), 3.65 (d, 1H), 4.15(q, 2H), 6.90 (s, 2H), 7.30 (m, 3H), 7.45 (d, 2H), 7.65 (s, 1H), 7.70(s, 1H), 11.00 (s, 1H).

Example 1052-[(Aminocarbonyl)amino]-5-[4-((3-diethylaminocarbonylpiperidin-1-yl)methyl)phenyl]-thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 103 (b)but starting from 3-([N,N-diethyl]carboxamido)piperidine.

MS (ES) 458 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (t, 3H), 1.05 (t, 3H), 1.35 (m, 1H), 1.45-1.65 (m,3H), 1.85 (m, 1H), 2.00 (t, 1H), 2.70 (m, 2H), 2.80 (m, 1H), 3.25 (m,4H), 3.45 (q, 2H), 6.90 (s, 2H), 7.30 (m, 3H), 7.45 (d, 2H), 7.65 (s,1H), 7.70 (s, 1H), 11.00 (s, 1H).

Example 1062-[(Aminocarbonyl)amino]-5-[4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl]thiophene-3-carboxamide

2-[(Aminocarbonyl)amino]-5-(4-formylphenyl)-3-thiophenecarboxamide (100mg) was stirred in a mixture of 1,2-dimethoxyethane (10 ml) andN,N-dimethylacetamide (5 ml). 3-pyrrolidinol (0.15 g) was added,followed by trimethyl orthoformate (5 ml) and acetic acid (0.5 ml). Thereaction was stirred at 80° C. for 20 minutes, and thenpolymer-supported cyanoborohydride (0.45 g) was added. The reaction wasstirred at 80° C. for a further 2 h, and then polymer-supportedbenzaldehyde (0.5 g) was added. The resins were removed by filtration,and the filtrate was then passed through a 5 g SCX column, washing withmethanol (25 ml). The product was eluted using 1M methanolic ammonia (45ml), and this solution was then evaporated to dryness under reducedpressure. Purification by chromatography on silica, eluting withdichloromethane/methanol (9:1), gave the product as an off-white solid(30 mg).

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 1.55 (m, 1H), 2.05 (m, 1H), 2.35 (m, 1H), 2.45 (m, 1H),2.60 (m, 1H), 2.70 (m, 1H), 3.55 (m, 2H), 4.20 (m, 1H), 4.65 (m 1H),6.90 (s, 2H), 7.30 (m, 3H), 7.50 (d, 2H), 7.70 (m, 2H), 10.95 (s, 1H).

Example 1072-[(Aminocarbonyl)amino]-5-[4-({(2-hydroxyethyl)piperazin-1-yl}methyl)phenyl]-thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 106 butusing 4-(2-hydroxyethyl)piperazine (CAS Registry No. 103-76-4).

MS (ES) 404 (M+H)⁺.

¹H NMR (DMSO-D6) 2.25-2.60 (m, 10H), 3.50 (m, 4H), 4.35 (m, 1H), 6.90(s, 2H), 7.30 (m, 3H), 7.45 (d, 2H), 7.70 (m, 2H), 10.95 (s, 1H).

Example 1082-[(Aminocarbonyl)amino]-4-methyl-5-{4-[4-morpholino]methylphenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using 1-bromo-4-(4-morpholino)methylbenzene and2-[(aminocarbonyl)amino]-5-bromo-4-methyl-3-thiophenecarboxamide. Thecrude solid was purified by cation exchange chromatography eluting withammonia/dichloromethane/methanol mixtures.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 2.25 (s, 3H), 2.3 (s, 4H), 3.5 (s, 2H), 3.55 (m, 4H),6.8 (s, 2H), 7.2-7.5 (m, 6H), 10.05 (s, 1H).

b) 2-[(Aminocarbonyl)amino]-4-methyl-3-thiophenecarboxamide

Prepared in a similar manner to Example 9 (b) except thattetrahydrofuran was used as solvent and the product was obtained bytrituration with methanol.

MS (ES) 198 (M−H)⁻, 200 (M+H)⁺.

¹H NMR (DMSO-D6) 2.2 (s, 3H), 6.35 (s, 1H), 6.65 (s, 2H), 6.8-8.3 (brs,2H), 10.3 (s, 1H).

c) 2-[(Aminocarbonyl)amino]-5-bromo-4-methyl-3-thiophenecarboxamide

Prepared in a similar manner to Example 9 (c) except that theprecipitated product was filtered off from the reaction and trituratedwith methanol.

MS (ES) 276, 278 (M−H)⁻, 278, 280 (M+H)⁺.

¹H NMR (DMSO-D6) 2.1 (s, 3H), 6.8 (s, 2H), 7.0-7.5 (brs, 2H), 10.15 (s,1H).

Example 1092-[(Aminocarbonyl)amino]-5-[4-((4-hydroxypiperidin-1-yl)methyl)phenyl]thiophene-3-carboxamidea) 1-(4-Bromobenzyl)piperidin-4-ol

4-Bromobenzylbromide (3 g) was stirred with 4-hydroxypiperidine (1.21 g)and potassium carbonate (1.99 g) in dimethylacetamide (15 ml) at 50° C.for 3 h The reaction mixture was then allowed to cool, poured into water(80 ml) and extracted with ethyl acetate (3×50 ml). The combinedextracts were washed with water, dried (MgSO₄), filtered and evaporated.The residue was purified by column chromatography, eluting with agradient of 0-3% methanol in dichloromethane, to afford the product as aviscous, colourless oil (2.02 g).

MS (ES) 270 (M+H)⁺.

¹H NMR (CDCl₃) 1.50-1.67 (m, 2H), 1.8-1.95 (m, 2H), 2.07-2.20 (m, 2H),2.66-2.77 (m, 2H), 3.44 (s, 2H), 3.65-3.77 (m, 1H), 7.19 (d, 2H), 7.43(d, 2H).

b)2-[(Aminocarbonyl)amino]-5-[4-((4-hydroxypiperidin-1-yl)methyl)phenyl]thiophene-3-carboxamide

The title compound was prepared from 1-(4-bromobenzyl)piperidin-4-ol ina similar manner to Example 38 (a), but was purified by preparativeHPLC.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.30-1.45 (m, 2H), 1.60-1.75 (m, 2H), 1.94-2.08 (m,2H), 2.58-2.70 (m, 2H), 3.30-3.50 (m, 2H), 4.49 (d, 1H), 6.92 (brs, 2H),7.26 (d, 2H), 7.26 (brs, 1H), 7.44 (d, 2H), 7.65 (brs, 1H), 7.66 (s,1H), 10.97 (s, 1H).

Example 1102-[(Aminocarbonyl)amino]-5-(2-piperazin-1-ylphenyl)thiophene-3-carboxamidea) 1-(2-Bromophenyl)-4-(t-butyloxycarbonyl)piperazine

1,2-Dibromobenzene (2.56 ml) was stirred in toluene (100 ml) and thesolution was purged with argon. 1-t-Butyloxycarbonylpiperazine (4.74 g),sodium t-butoxide (2.85 g), BINAP (95 mg) and palladium acetate (50 mg)were added. The reaction mixture was stirred at 80° C. under argon for16 h, then allowed to cool. Insoluble material was removed by filtrationand washed with toluene. The solvent was evaporated and the residue waspurified by column chromatography, eluting with hexane, to give theproduct as a pale yellow oil (1.85 g).

MS (ES) 341 (M+H)⁺.

¹H NMR (CDCl₃) 1.50 (s, 9H), 2.90-3.04 (m, 4H), 3.55-3.65 (m, 4H), 6.92(td, 1H), 7.01 (dd, 1H), 7.21-7.29 (m, 1H), 7.56 (dd, 1H).

b)2-[(Aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazin-1-yl)phenyl]thiophene-3-carboxamide

The title compound was prepared from1-(2-bromophenyl)-4-(t-butyloxycarbonyl)-piperazine in a similar mannerto Example 9 (e), except that on work-up the reaction mixture wasevaporated and the residue taken up in dichloromethane and 2M aqueoussodium hydroxide. The aqueous phase was washed with a further portion ofdichloromethane and the combined organic layers were evaporated in vacuothen purified by cation exchange chromatography, eluting with 5-10%methanol in dichloromethane. Fractions containing product wereevaporated, the residue was triturated with ether and the solid productcollected by filtration.

MS (ES) 446 (M+H)⁺.

¹H NMR (DMSO-D6) 1.40 (s, 9H), 2.72-2.83 (m, 4H), 3.47-3.57 (m, 4H),6.80 (brs, 2H), 7.07-7.25 (m, 4H), 7.56 (d, 1H), 7.65 (brs, 1H), 7.75(s, 1H), 10.90 (s, 1H).

c)2-[(Aminocarbonyl)amino]-5-[2-(piperazin-1-yl)phenyl]thiophene-3-carboxamide

2-[(Aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazin-1-yl)phenyl]thiophene-3-carboxamide(64 mg) was stirred in dichloromethane (4 ml). Trifluoroacetic acid (1ml) was added and the solution was stirred at room temperature for 1 h.The volatile materials were removed in vacuo; the residue was dilutedwith water (2 ml) and basified with a few drops of aqueous ammonia. Theprecipitated product was collected by filtration and washed with water.The gummy solid obtained was dissolved in methanol, the solvent wasevaporated and the residue triturated with a mixture of methanol andether and then filtered to give the product as an off-white solid (20mg).

MS (ES) 346 (M+H)⁺.

¹H NMR (DMSO-D6, 400 MHz) 2.75-2.85 (m, 4H), 2.95-3.05 (m, 4H), 6.80(brs, 2H), 7.08-7.30 (m, 4H), 7.55 (d, 1H), 7.62 (brs, 1H), 7.72 (s,1H), 10.91 (s, 1H).

Example 1112-[(Aminocarbonyl)amino]-5-[2-(4-methylpiperazin-1-yl)phenyl]thiophene-3-carboxamidea) 1-(2-Bromophenyl)-4-methylpiperazine

The title compound was prepared from dibromobenzene and1-methylpiperazine in a similar manner to Example 110 (a).

MS (ES) 255 (M+H)⁺.

¹H NMR (CDCl₃) 2.35 (s, 3H), 2.50-2.70 (m, 4H), 2.98-3.15 (m, 4H), 6.90(td, 1H), 7.05 (dd, 1H), 7.26 (td, 1H, 7.55 (dd, 1H).

b)2-[(Aminocarbonyl)amino]-5-[2-(4-methylpiperazin-1-yl)-phenyl]thiophene-3-carboxamide

The title compound was prepared from1-(2-bromophenyl)-4-methylpiperazine in a similar manner to Example 9(e), except that the product was purified by cation exchangechromatography, eluting with 0-10% of 2M ammonia/methanol indichloromethane. Fractions containing product were evaporated,triturated with ether and the product was collected by filtration.

MS (ES) 360 (M+H)⁺.

¹H NMR (DMSO-D6) 2.20 (s, 3H), 2.45-2.58 (m, 4H), 3.30 (s, 4H), 6.81(brs, 2H), 7.05-7.24 (m, 4H), 7.53 (d, 1H), 7.62 (brs, 1H), 7.70 (s,1H), 10.90 (s, 1H).

Example 1122-[(Aminocarbonyl)amino]-5-{2-[3-methylamino)pyrrolidin-1-yl]phenyl}thiophene-3-carboxamidea) 1-(2-Bromophenyl)-[3-(N-t-butyloxycarbonyl-N-methylamino)]pyrrolidine

The title compound was prepared from dibromobenzene and3-(N-t-butyloxycarbonyl-N-methylamino)pyrrolidine as for Example 110(a).

MS (ES) 355 (M+H)⁺.

¹H NMR (CDCl₃) 1.48 (s, 9H), 1.90-2.05 (m, 1H), 2.15-2.30 (m, 1H), 2.93(s, 3H), 3.10-3.22 (m, 2H), 3.40-3.50 (m, 1), 3.55 (dd, 1H), 4.80-4.95(brm, 1H), 6.83 (td, 1H), 6.95 (dd, 1H), 7.22 (td, 1H), 7.52 (dd, 1H).

b)2-[Aminocarbonyl)amino]-5-{2-[3-(N-t-butyloxycarbonyl-N-methylamino)pyrrolidin-1-yl]phenyl}thiophene-3-carboxamide

The title compound was prepared from1-(2-bromophenyl)-[3-(N-t-butyloxycarbonyl-N-methylamino)]pyrrolidine ina similar manner to Example 9 (e), except that on work-up the reactionmixture was evaporated to dryness, taken up in dichloromethane and 2Maqueous sodium hydroxide and the layers were separated. The organicphase was concentrated in vacuo and purified by cation exchangechromatography, eluting with a gradient of 0-4% 2M ammonia/methanol indichloromethane. Fractions containing product were evaporated and theproduct triturated with ether and collected by filtration.

MS (ES) 460 (M+H)⁺.

¹H NMR (DMSO-D6) 1.38 (s, 9H), 1.79-2.09 (m, 2H), 2.70-3.18 (m, 4H),2.75 (s, 3H), 4.65-4.80 (brm, 1H), 6.85 (brs, 2H), 6.95 (t, 1H), 7.05(d, 1H), 7.13-7.24 (m, 2H), 7.34 (d, 1H), 7.46 (s, 1H), 7.60 (brs, 1H),10.94 (s, 1H).

c)2-[(Aminocarbonyl)amino]-5-{2-[3-methylamino)pyrrolidin-1-yl]phenyl}thiophene-3-carboxamide

2-[Aminocarbonyl)amino]-5-{2-[3-(N-t-butyloxycarbonyl-N-methylamino)pyrrolidin-1-yl]phenyl}thiophene-3-carboxamide(187 mg) was stirred in dichloromethane (2 ml). Trifluoroacetic acid (2ml) was added dropwise and stirring continued at room temperature for 10h. The volatile materials were evaporated in vacuo and the residuepurified by cation exchange chromatography, eluting with a gradient of0-10% 2M ammonia/methanol in dichloromethane. Fractions containingproduct were evaporated, triturated with ether and the product collectedby filtration (88 mg).

MS (ES) 360 (M+H)⁺.

¹H NMR (DMSO-D6) 1.55-1.70 (m 1H), 1.95-2.10 (m, 1H), 2.21 (s, 3H),2.74-3.10 (m, 4H), 3.95-4.10 (brm, 1H), 6.83 (brs, 2H), 6.90 (t, 1H),6.99 (d, 1H), 7.10-7.22 (m, 2H), 7.30 (d, 1H), 7.42 (s, 1H), 7.60 (brs,1H), 10.93 (brs, 1H).

Example 1132-[(Aminocarbonyl)amino]-5-[4-(cyclopentyloxy)-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from1-{2-[2-bromo-5-(cyclopentyloxy)phenoxy]-ethyl}piperidine in a similarmanner to Example 43 except that the residue was extracted with hotethyl acetate (2×100 ml), evaporated to give a gum which was purified bycolumn chromatography eluting with methanol/dichloromethane/0.88 ammonia1/9/0.01. Further column chromatography eluting with a gradient usingwater/acetonitrile/trifluoroacetic acid gave on triturating with ammoniathe product as a light brown solid (20 mg).

MS (ES) 473 (M+H)⁺.

¹H NMR (DMSO-D6) 1.34 (m, 2H), 1.45 (m, 4H), 1.57 (m, 2H), 1.69 (m, 4H),1.90 (m, 2H), 2.44 (m, 4H), 2.74 (t, 2H), 4.11 (t, 2H), 4.84 (m, 1H),6.52 (d, 1H), 6.58 (d, 1H), 6.77 (brs, 2H), 7.15 (brs, 1H), 7.42, (d,1H), 7.54 (s+brs, 2H), 10.86 (s, 1H).

b) 1-{2-[2-Bromo-5-(cyclopentyloxy)phenoxy]ethyl}piperidine

4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenol (1.5 g), bromocyclopentane(0.59 ml) and anhydrous potassium carbonate (1.04 g) were stirred andheated at 80° C. in dimethylformamide for 18 h. The mixture waspartitioned between ethyl acetate (100 ml) and water (70 ml). Theaqueous was extracted further with ethyl acetate (100 ml) and thecombined organics were washed with 2N sodium hydroxide solution (50 ml),water (50 ml), brine (50 ml), dried (MgSO₄) and evaporated to give theproduct as an oil (1.5 g).

MS (ES) 368 (M+H)⁺.

¹H NMR (CDCl₃) 1.38 (m, 2H), 1.54 (m, 4H), 1.68-1.86 (m, 8H), 2.50 (m,4H), 2.77 (t, 2H), 4.05 (t, 2H), 4.63 (m, 1H), 6.29 (d, 1H), 6.37 (d,1H), 7.29 (d, 1H).

c) 4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenol

4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl 4-methylbenzenesulfonate(24.2 g), potassium hydroxide (16.1 g), water (96 ml) and ethanol (860ml) were heated on the steam bath for 2 h. The pH was adjusted to 4 withconcentrated hydrochloric acid, then to pH 7 with solid sodiumbicarbonate. After evaporation to near dryness, water (200 ml) was addedand the mixture was extracted with ethyl acetate (3×150 ml). The organicphase was washed with water, brine, dried (MgSO₄) and evaporated to givean oil (16.4 g).

MS (ES) 300 (M+H)⁺.

¹H NMR (CDCl₃) 1.47 (m, 2H), 1.64 (m, 4H), 2.66 (m, 4H), 2.87 (t, 2H),4.06 (t, 2H), 6.31 (m, 2H), 7.25 (d, 1H).

d) 4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl 4-methylbenzenesulfonate

4-Bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (17.6 g), potassiumcarbonate (7.32 g), 1-(2 chloroethyl)piperidine hydrochloride (9.2 g)and acetone (300 ml) were stirred at reflux for 3 h, the reactionmixture filtered and evaporated to give the product as light brown foam(24.2 g).

MS (ES) 454 (M+H)⁺.

¹H NMR (CDCl₃) 1.38 (m, 2H), 1.53 (m, 4H), 2.38 (s, 3H), 2.45 (t, 4H),2.71 (t, 2H), 3.94 (t, 2H), 6.35 (d, 1H), 6.51 (d, 1H), 7.25 (d, 2H),7.32 (d, 1H), 7.64 (d, 2H). The structure was confirmed by n.O.e.experiments.

Example 1142-[(Aminocarbonyl)amino]-5-[2-(2-{piperidin-1-yl}ethoxy-4-pyrrolidin-1-ylphenyl]thiophene-3-carboxamide

a) The title compound was prepared from1-[2-(2-bromo-5-pyrrolidin-1-ylphenoxy)ethyl]piperidine in a similarmanner to Example 113 (a) except that the product was obtained bytriturating with ether to give a light brown solid (20 mg).

MS (ES) 458 (M+H)⁺.

¹H NMR (DMSO-D6) 1.36 (m, 2H), 1.48 (m, 4H), 1.93 (m, 4H), 2.45 (m, 4H),2.77 (t, 2H), 3.26 (m, 4H), 4.12 (t, 2H), 6.16 (m, 2H), 6.73 (brs, 2H),7.12 (brs, 1H), 7.31 (d, 1H), 7.41 (s, 1H), 7.50 (brs, 1H), 10.82 (s,1H).

b) 1-[2-(2-Bromo-5-pyrrolidin-1-ylphenoxy)ethyl]piperidine

4-Bromo-3-(2-{piperidin-1-yl}ethoxy)aniline (2.99 g), 1,4-dibromobutane(1.2 ml), diisopropylethylamine (4.18 ml) and toluene (15 ml) werestirred and heated at 110° C. for 18 h. When cool, water (20 ml) wasadded, and the mixture was extracted with ethyl acetate (2×30 ml). Thecombined organic phase was washed with water, brine, dried (MgSO₄) andevaporated to give the product as an orange-brown oil (2.25 g).

MS (ES) 353 (M+H)⁺.

¹H NMR (CDCl₃) 1.37 (m, 2H), 1.53 (m, 4H), 1.92 (m, 4H), 2.48 (t, 4H),2.76 (t, 2H), 3.17 (t, 4H), 4.07 (t, 2H), 5.97 (dd, 1H), 6.03 (d, 1H),7.19 (d, 1H).

c) 4-Bromo-3-(2-{piperidin-1-yl}(ethoxy)aniline

N-[4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl]acetamide (17.48 g), 35%hydrochloric acid (100 ml) and water (100 ml) were heated at 95° C. for2 h, evaporated to near dryness, water (100 ml) added and the pHadjusted to 8 with sodium carbonate. Extraction with dichloromethane(3×200 ml), the combined organic phase washed with water, brine, dried(MgSO₄) and evaporated to give the product as a solid (13.64 g).

MS (ES) 299 (M+H)⁺.

¹H NMR (CDCl₃) 1.38 (m, 2H), 1.53 (m, 4H), 2.48 (m, 4H), 2.75 (t, 2H),3.60 (brs, 2H), 4.02 (t, 2H), 6.10 (dd, 1H), 6.18 (d, 1H), 7.16 (d, 1H).

d) N-[4-Bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl]acetamide

N-(4-Bromo-3-hydroxyphenyl)acetamide (19.4 g), anhydrous potassiumcarbonate (25.6 g), 1-(2 chloroethyl)piperidine hydrochloride (15.78 g)and acetone (400 ml) were heated at reflux for 18 h, filtered andevaporated to dryness to give the product as a solid (17.48 g).

MS (ES) 341 (M+H)⁺.

¹H NMR (DMSO-D6) 1.36 (q, 2H), 1.48 (m, 4H), 2.02 (s, 3H), 2.45 (m, 4H),2.67 (t, 2H), 4.04 (t, 2H), 7.07 (d, 1H), 7.43 (s+d, 2H), 10.02 (s, 1H).

Example 1152-[(Aminocarbonyl)amino]-5-[4-piperidin-1-yl-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from1-[4-bromo-3-(2-{piperidin-1-yl}ethoxy)phenyl]piperidine in a similarmanner to Example 114 (a) to give the product as a solid (20 mg).

MS (ES) 472 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 2H), 1.46 (ma, 4H), 1.59 (m, 6H), 2.44 (m,4H), 2.75 (t, 2H), 3.17 (m, 4H), 4.12 (t, 2H), 6.53 (dd, 1H), 6.57 (s,1H), 6.75 (brs, 2H), 7.12 (brs, 1H), 7.36 (d, 1H), 7.49 (s, 1H), 7.51(brs, 1H), 10.84 (s, 1H).

b) 1-[4-Bromo-3-(2-piperidin-1-ylethoxy)phenyl]piperidine

The title compound was prepared as in Example 114 (b) using1,5-dibromopentane except that the oil obtained was purified by columnchromatography eluting with methanol/dichloromethane 1:9 to give theproduct as an oil (2.1 g).

MS (ES) 367 (M+H)⁺.

¹H NMR (CDCl₃) 1.43 (m, 2H), 1.52 (m, 2H), 1.62 (m, 8H), 2.62 (m, 4H),2.87 (t, 2H), 3.06 (m, 4H), 4.14 (t, 2H), 6.35 (dd, 1H), 6.43 (s, 1H),7.24 (d, 1H).

Example 1162-[(Aminocarbonyl)amino]-5-[4-(morpholin-4-ylmethyl)-2-(2-{piperidin-1-yl}ethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-[4-bromo-3-(2-{piperidin-1-yl}ethoxy)-benzyl]morpholine (1.95 g) in asimilar manner to Example 43 to give a fawn solid (60 mg).

MS (ES) 488 (M+H)⁺.

¹H NMR (DMSO-D6) 1.36 (m, 2H), 1.48 (m, 4H), 2.33 (m, 4H), 2.42 (m, 4H),2.63 (t, 2H), 3.43 (s, 2H), 3.56 (m, 4H), 4.06 (t, 2H), 6.85 (dd+brs,3H), 7.02 (d, 1H), 7.21 (s+brs, 2H), 7.25 (d, 1H), 7.56 (brs, 1H), 10.91(s, 1H).

b) 4-[4-Bromo-3-(2-piperidin-1-ylethoxy)benzyl]morpholine

The title compound was prepared from 2-bromo-5-(morpholinylmethyl)phenol(4.75 g) in a similar manner to Example 114 (d) except that the productwas purified by column chromatography eluting with dichloromethane and1:9 methanol/dichloromethane to give an oil (2.28 g).

MS (ES) 383 (M+H)⁺.

¹H NMR (CDCl₃) 1.37 (m, 2H), 1.54 (m, 4H), 2.44 (m, 8H), 2.68 (t, 2H),3.47 (s, 2H), 3.65 (m, 4H), 4.01 (t, 2H), 6.61 (dd, 1H), 7.00 (d, 1H),7.33 (d, 1H).

c) 2-Bromo-5-(morpholin-4-ylmethyl)phenol

3-(Morpholin-4-ylmethyl)phenol (9.65 g) in glacial acetic acid (60 ml)was treated over 2 h with bromine (2.88 ml) in acetic acid (8 ml),evaporated to near dryness, water (100 ml) added and basified with 0.880ammonia, extracted with ethyl acetate, washed with water, brine, dried(MgSO₄) and evaporated to dryness to give an oil, which was purified bycolumn chromatography eluting with 1:1 ether/isohexane to give thedesired product as an oil (4.75 g).

MS (ES) 272 (M+H)⁺.

¹H NMR (CDCl₃) 2.47 (t, 4H), 3.47 (s, 2H), 3.67 (t, 4H), 6.54 (dd, 1H),6.94 (d, 1H), 7.30 (d, 1H).

Example 1172-[(Aminocarbonyl)amino]-5-[4-(2-methoxyethoxy)-2-(2-piperidin-1-ylethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared in a similar manner to Example 113(a) from 1-{2-[2-bromo-5-(2-methoxyethoxy)phenoxy]ethyl}piperidine (1.35g) except that the residue was purified by reversed phase chromatographyeluting with water/acetonitrile/trifluoroacetic acid, then furthercolumn chromatography with methanol/dichloromethane/0.88 ammonia to givethe product as a fawn solid (80 mg).

MS (ES) 463 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 2H), 1.47 (m, 4H), 2.45 (m, 4H), 2.77 (t, 2H),3.30 (s, 3H), 3.64 (m, 2H), 4.12 (m, 4H), 6.57 (dd, 1H), 6.66 (d, 1H),6.79 (brs, 2H), 7.16 (brs, 1H), 7.44 (d, 1H), 7.55 (s+brs, 2H), 10.86(s, 1H).

b) 1-{2-[2-Bromo-5-(2-methoxyethoxy)phenoxy]ethyl}piperidine

This was prepared in a similar manner to Example 113 (b) using1-bromo-2-methoxyethane (0.52 ml) to give the product as an oil (1.35g).

MS (ES) 358 (M+H)⁺.

¹H NMR (CDCl₃) 1.31 (m, 2H), 1.53 (m, 4H), 2.48 (t, 4H), 2.76 (t, 2H),3.37 (s, 3H), 3.66 (t, 2H), 4.03 (dt, 4H), 6.33 (d, 1H), 6.47 (s, 1H),7.30 (d, 1H).

Example 1182-[(Aminocarbonyl)amino]-5-[4-morpholin-4-yl-2-(2-piperidin-1-ylethoxy)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-[4-bromo-3-(2-piperidin-1-ylethoxy)phenyl]morpholine (1.85 g) in asimilar manner to Example 43 except that the product was purified bycolumn chromatography eluting with methanol/dichloromethane/0.880ammonia 95:5:0.1 to give the product as a fawn solid (146 mg).

MS (ES) 474 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 2H), 1.46 (m, 4H), 2.44 (m, 4H), 2.75 (t, 2H),3.14 (m, 4H), 3.71 (m, 4H), 4.13 (t, 2H), 6.55 (dd, 1H), 6.59 (d, 1H),6.76 (brs, 2H), 7.15 (brs, 1H), 7.40 (d, 1H), 7.53 (brs+s, 2H), 10.85(s, 1H).

b) 4-[4-Bromo-3-(2-piperidin-1-ylethoxy)phenyl]morpholine

The title compound was prepared in a similar manner to Example 114 (b)but using 1-bromo-2-(2-bromoethoxy)ethane (1.4 ml) to give the productas an oil (2.30 g).

MS (ES) 369 (M+H)⁺.

¹H NMR (CDCl₃) 1.38 (m, 2H), 1.54 (m, 4H), 2.50 (t, 4H), 2.77 (t, 2H),3.05 (t, 4H), 3.77 (t, 4H), 4.07 (t, 2H), 6.31 (dd, 1H), 6.40 (d, 1H),7.29 (d, 1H).

Example 1192-[(Aminocarbonyl)amino]-5-[2-(2-hydroxyethoxy)phenyl]thiophene-3-carboxamide

The title compound was prepared from[2-(2-bromophenoxy)ethoxy]-(tert-butyl)dimethylsilane (1.68 g) in asimilar manner to Example 43 except that the dichloromethane extract waspurified by column chromatography eluting with dichloromethane, then 1:9methanol/dichloromethane, then further preparative HPLC to give theproduct as a solid on triturating with ether (142 mg).

MS (ES) 322 (M+H)⁺.

¹H NMR (DMSO-D6) 3.84 (q, 2H), 4.13 (t, 2H), 4.82 (t, 1H), 6.86 (brs,2H), 7.00 (t, 1H), 7.12 (d, 1H), 7.22 (t+brs, 2H), 7.57 (d+brs, 2H),7.80 (s, 1H), 10.95 (s, 1H).

b) [2-(2-Bromophenoxy)ethoxy](tert-butyl)dimethylsilane

2-Bromophenol (1.88 g), anhydrous potassium carbonate (1.51 g),(2-bromoethoxy)-(tert-butyl)dimethylsilane (2.61 g) anddimethylformamide (30 ml) were heated for 20 h at 90° C., cooled, pouredinto water (100 ml), extracted with ethyl acetate, the organic phasewashed with water, brine, dried (MgSO₄) and evaporated to dryness. Theresidue was purified by column chromatography eluting with 1:9ether/isohexane to give the product as a crystalline solid (1.68 g).

¹H NMR (CDCl₃) 0.04 (s, 6H), 0.84 (s, 9H), 3.95 (t, 2H), 4.03 (t, 2H),6.75 (t, 1H), 6.86 (d, 1H), 7.17 (t, 1H), 7.45 (d, 1H).

Example 120(3R)-2-[(Aminocarbonyl)amino]-5-{2-[tetrahydrofuran-3-yloxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using R-3-(2-bromophenoxy)tetrahydrofuran.

MS (ES) 346 (M−H)⁻, 348 (M+H)⁺.

¹H NMR (DMSO-D6) 2.1-2.3 (m, 2H), 3.7-4.0 (m, 4H), 5.1 (m, 1H), 6.8(brs, 2H), 6.9-7.1 (m, 2H), 7.2 (m, 2H), 7.6 (m, 2H), 7.7 (s, 1H), 10.9(s, 1H).

b) R-3-(2-Bromophenoxy)tetrahydrofuran

Di-isopropylazodicarboxylate (5.5 g) was added dropwise at 0-5° C. to astirred solution of 2-bromophenol (4.0 g), triphenylphosphine (7.1 g)and S-3-hydroxytetrahydrofuran (2.4 g) in dry tetrahydrofuran (60 ml).The mixture was stirred for 18 h at 20° C., the solvent was evaporated,and the residue stirred in ether (150 ml) for 2 h, giving a whiteprecipitate. This was removed by filtration and the mother liquors werewashed with 2N sodium hydroxide solution, water, brine, evaporated, andthe residue was purified by column chromatography on silica eluting with10 to 50% ethyl acetate in isohexane, giving the title compound as acolourless oil (4.5 g).

MS (EI) 242 (M⁺).

¹H NMR (CDCl₃) 2.1-2.3 (m, 2H), 3.9-4.1 (m, 4H), 4.95 (m, 1H), 6.8-6.9(m, 2H), 7.2-7.3 (m, 1H), 7.5-7.6 (d, 1H).

Example 121(3S)-2-[(Aminocarbonyl)amino]-5-{2-[tetrahydrofuran-3-yloxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using S-3-(2-bromophenoxy)tetrahydrofuran.

MS (ES) 346 (M−H)⁻, 348 (M+H)⁺.

¹H NMR (DMSO-D6) 2.1-2.3 (m, 2H), 3.7-4.0 (m, 4H), 5.1 (m, 1H), 6.8(brs, 2H), 6.9-7.1 (m, 2H), 7.2 (m, 2H), 7.6 (m, 2H), 7.7 (s, 1H), 10.9(s, 1H).

b) S-3-(2-Bromophenoxy)tetrahydrofuran

The compound was prepared from R-3-hydroxytetrahydrofuran in a similarmanner to Example 120 (b).

MS (EI) 242, 244 (M⁺).

¹H NMR (CDCl₃) 2.1-2.3 (m, 2H), 3.9-4.1 (m, 4H), 4.95 (m, 1H), 6.8-6.9(m, 2H), 7.2-7.3 (m, 1H), 7.5-7.6 (d, 1H).

Example 1222-[(Aminocarbonyl)amino]-5-{2-[(tetrahydropyran-4-yloxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using 4-(2-bromophenoxy)-tetrahydropyran.

MS (ES) 360 (M−H)⁻, 362 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65-1.8 (m, 2H), 1.9-2.05 (m, 2H) 3.4-3.5 (m, 2H)3.85-3.95 (m, 2H), 4.7 (m, 1H), 6.8 (brs, 2H), 6.95 (t, 1H), 7.1-7.2 (m,3H), 7.6-7.65 (m, 2H), 7.7 (s, 1H), 10.9 (s, 1H).

b) 4-(2-Bromophenoxy)tetrahydropyran

The compound was prepared from 4-hydroxytetrahydropyran in a similarmanner to Example 120 (b).

MS (EI) 256, 258 (M⁺).

¹H NMR (CDCl₃) 1.8-1.9 (m, 2H), 1.95-2.1 (m, 2H), 3.5-3.7 (m, 2H),3.95-4.05 (m, 2H), 4.5-4.6 (m, 1H), 6.85 (t, 1H), 6.9 (d, 1H), 7.2 (d,1H), 7.55 (d, 1H).

Example 1232-[(Aminocarbonyl)amino]-5-{2-[cyclopropylmethoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using 1-bromo-2-(cyclopropylmethoxy)benzene.

MS (ES) 330 (M−H), 332 (M+H)⁺.

¹H NMR (DMSO-D6) 0.0, (d, 2H), 0.1 (d, 2H), 0.9 (m, 1H), 3.55 (d, 2H),6.4 (brs, 2H), 6.6 (t, 1H), 6.65 (d, 1H), 6.7-6.9 (m, 2H), 7.2 (m, 2H),7.4 (s, 1H), 10.55 (s, 1H).

b) 1-Bromo-2-(cyclopropylmethoxy)benzene

Prepared from cyclopropylmethyl bromide and 2-bromophenol by the methodof Example 42 (b) except that the reaction mixture was stirred at 75° C.for 4 h. This gave the product as a colourless oil.

MS (EI) 226, 228 (M⁺).

¹H NMR (CDCl₃) 0.35-0.4 (m, 2H), 0.6-0.7 (m, 2H), 1.3 (m, 1H), 3.9 (d,2), 6.8 (t, 1H), 6.9 (t, 1H), 7.1 (d, 1H), 7.55 (d, 1H).

Example 1242-[(Aminocarbonyl)amino]-5-{2-[cyclopentyloxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using 1-bromo-2-(cyclopentyloxy)benzene.

MS (ES) 344 (M−H)⁻, 346 (M+H)⁺.

¹H NMR (DMSO-D6) 1.5-1.7 (m, 2H), 1.8-1.95 (m, 6H), 4.95 (m, 1H), 6.8(s, 2H), 6.9 (t, 1H), 7.0 (d, 1H), 7.3 (m, 2H), 7.6 (m, 2H), 7.7 (s,1H), 10.9 (s, 1H).

b) 1-Bromo-2-(cyclopentyloxy)benzene

This was prepared from cyclopentanol in a similar manner to Example 120(b).

MS (EI) 240, 242 (M⁺).

¹H NMR (CDCl₃) 1.6-1.7 (m, 2H), 1.8-2.0 (m, 6H), 4.8 (m, 1H), 6.8 (t,1H), 6.9 (d, 1H), 7.2 (t, 1H), 7.5 (d, 1H).

Example 1252-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The compound was made from 3-(2-bromophenoxy)-1-isopropylpyrrolidineby a similar manner to Example 10 (e), except that the triisopropylborate was added after adding the butyl lithium solution in the firststep, the solvent for the second step was dimethoxyethane/water (10:1)and solid sodium hydrogen carbonate was used and that the solid productwas purified by ion exchange chromatography to yield the product (42mg).

MS 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 2.0 (m, 1H), 2.2 (m, 1H), 2.4 (m, 1H), 2.6(m, 1H), 2.75 (m, 2H), 3.0 (m, 1H), 5.0 (m, 1H), 6.85 (brs, 2H), 7.0 (m,2H), 7.15 (t, 1H), 7.2 (brs, 1H), 7.6 (m, 2H), 7.75 (s, 1H), 10.9 (s,1H).

b) 3-(2-Bromophenoxy)-1-isopropylpyrrolidine

To a solution of 2-bromophenol (2.6 g) in dimethylacetamide (20 ml) wasadded sodium hydride (640 mg) portionwise. A solution of1-isopropylpyrrolidin-3-yl methanesulphonate [Example 134 (c)] indimethylacetamide (20 ml) was added and the mixture was heated to 150°C. for 18 h. The mixture was allowed to cool and partitioned betweenwater and dichloromethane. The organic phase was extracted with 2Naqueous hydrochloric acid which was then neutralised and extracted withdichloromethane. The extracts were dried (MgSO₄), the solvent removedunder vacuum and the product purified by silica chromatography usingdichloromethane/aqueous ammonia/methanol mixtures to yield the titlecompound as a brown oil (496 mg).

MS 284 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.8 (m, 1H), 2.2 (m, 1H), 2.35-2.6 (m, 2Hobscured), 2.7 (m, 2H), 3.0 (m, 1H), 4.9 (m, 1H), 6.9 (t, 1H), 7.05 (d,1H), 7.3 (t, 1H), 7.55 (d, 1H).

Example 1262-[(Aminocarbonyl)amino]-5-{2-[(1-ethylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromophenoxy)-1-ethylpyrrolidine in a similar manner to Example 43(a).

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (t, 3H), 1.95 (m, 1H), 2.25 (m, 1H), 2.5 (m,obscured), 2.7 (m, 1H), 3.0 (m, 1H), 4.95 (m, 1H), 6.8 (s, 2H), 6.9-7.1(m, 3H), 7.2 (m, 2H), 7.5-7.7 (m, 3H), 7.75 (s, 1H), 10.9 (s, 1H).

b) 3-(2-Bromophenoxy)-1-ethylpyrrolidine

1-Ethyl-3-pyrrolidinol (0.5 ml), 2-bromophenol (0.37 ml) andtriphenylphosphine (1.02 g) were dissolved in tetrahydrofuran (10 ml)and the mixture cooled in an ice bath before dropwise addition ofdiisopropyl azodicarboxylate (0.77 ml). The mixture was allowed to warmto room temperature over 3 h. The mixture was concentrated in vacuo andpartitioned between ether (50 ml) and water (50 ml) and the aqueousphase was extracted further with ether (50 ml). The combined organicphases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO₄)and concentrated in vacuo. The product was dissolved in ethyl acetate(50 ml) and extracted with 2M aqueous hydrochloric acid (3×20 ml). Theaqueous washings were combined and basified by the addition of solidsodium hydroxide and extracted with ethyl acetate (3×20 ml), dried(MgSO₄) and concentrated in vacuo. The residue was purified by cationexchange chromatography eluting with ammonia/methanol/dichloromethanemixtures. This gave the title compound as a pale orange oil (529 mg).

MS (ES) 270 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (t, 3H), 1.8 (m, 1H), 2.25 (m, 1H), 2.4 (m, 3H),2.65 (m, 2H), 2.9 (m, 1H), 4.9 (m, 1H), 6.9 (m, 1H), 7.05 (d, 1H), 7.3(t, 1H), 7.55 (d, 1H).

Example 1272-[(Aminocarbonyl)amino]-5-{2-[(1-tert-butyloxycarbonyl-3-pyrrolidinyl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from 1-tert-butyloxycarbonyl3-(2-bromophenoxy)-pyrrolidine in a similar manner to Example 9 (e).

MS (ES) 445 (M−H)⁻.

¹H NMR (DMSO-D6) 1.35 (s, 9H), 3.4-3.9 (m, obscured), 5.15 (s, 1H), 6.8(bs, 2H), 7.05 (t, 1H), 7.1 (m, 1H), 7.2 (m, 2H), 7.6-7.7 (brs, 1H),7.65 (d, 1H), 7.75 (s, 1H), 10.9 (s, 1H).

b) 3-(2-Bromophenoxy)-1-(tert-butyloxycarbonyl)pyrrolidine

3-(2-Bromophenoxy)pyrrolidine (1 g) was dissolved in methanol (50 ml)and di-tert-butyl dicarbonate (992 mg) was added. The reaction mixturewas stirred for 1 h and the reaction mixture concentrated in vacuoyielding a pale orange oil that solidified to white solid on standing(1.5 g).

MS (ES) 342 (M+H)⁺.

¹H NMR (DMSO-D6) 1.2 (s, 9H), 2.1 (m, 2H), 3.2-3.6 (m, obscured), 5.15(s, 1H), 6.9 (m, 1H), 7.15 (m, 1H), 7.35 (m, 1H), 7.55 (dd, 1H).

c) 3-(2-Bromophenoxy)pyrrolidine

1-tert-Butyloxycarbonyl-3-hydroxypyrrolidine (1 g), 2-bromophenol (710mg) and triphenylphosphine (1.29 g) were dissolved in tetrahydrofuran(15 ml) and the mixture cooled in an ice bath before dropwise additionof diisopropyl azodicarboxylate (0.96 ml). The mixture was allowed towarm to room temperature over 3 h, concentrated in vacuo, partitionedbetween ether (50 ml) and water (50 ml) and the aqueous phase wasextracted further with ether (50 ml). The combined organic phases werewashed with water (2×25 ml), brine (2×25 ml), dried (MgSO₄) andconcentrated in vacuo. The product was dissolved in dichloromethane (10ml) and trifluoroacetic acid (5 ml) was added and the reaction stirredfor 1 h. The mixture was concentrated in vacuo and the residue waspurified by cation exchange chromatography eluting withammonia/methanol/dichloromethane mixtures. This gave the title compoundas a pale orange oil (437 mg).

MS (ES) 242 (M+H)⁺.

¹H NMR (DMSO-D6) 1.75 (m, 1H), 2.0 (m, 1H), 2.75-3.2 (m, obscured), 4.9(m, 1H), 6.85 (m, 1H), 7.1 (m, 1H), 7.3 (m, 1H), 7.5 (m, 1H).

d) 1-tert-Butyloxycarbonyl-3-hydroxypyrrolidine

The title compound was prepared from pyrrolidin-3-ol (2 g) in a similarmanner to Example 127 (b) except the product was dissolved in diethylether (50 ml) washed with water (3×20 ml), brine (2×20 ml), dried(MgSO₄) and concentrated in vacuo to yield a clear oil (3.5 g).

MS (ES) 188 (M+H)⁺.

¹H NMR (DMSO-D6) 1.2 (s, 9H), 1.6-1.9 (m, 2H), 3.2-3.4 (m, obscured),4.2 (m, 1H).

Example 1282-[(Aminocarbonyl)amino]-5-[2-pyrrolidin-3-yloxy)phenyl]-3-thiophenecarboxamide

2-[(Aminocarbonyl)amino]-5-{2-[(1-tert-butyloxycarbonylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide(200 mg) was suspended in dichloromethane (30 ml) and trifluoroaceticacid (5 ml) was added. The mixture was stirred for 1 h, followed byconcentration in vacuo. The product was treated with 38% aqueous ammoniaand then isolated by filtration as a brown powder (98 mg).

MS (ES) 347 (M+H)⁺.

¹H NMR (DMSO-D6) 1.8-2.0 (m, 2H), 2.7 (m, 1H), 2.8-3.1 (m, 4H), 4.9 (s,1H), 6.8 (brs, 2H), 6.9 (m, 1H), 7.0 (m, 1H), 7.15 (m, 2H), 7.5-7.7 (m,2H), 7.7 (s, 1H), 10.9 (s, 1H).

Example 1292-[(Aminocarbonyl)amino]-5-{2-[(1-methylpiperidin-2-yl)methoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was made from2-[(2-bromophenoxy)methyl]-1-methylpiperidine in a similar manner toExample 43 (a).

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.4-1.9 (m, 6H), 2.0-2.1 (m, 1H), 2.35 (s, 3H), 2.65(m, 1H), 2.8 (m, 1H), 2.9 (m, 1H), 4.7 (m, 1H), 6.85 (brs, 2H), 7.0 (m,1H), 7.1 (m, 1H), 7.25 (m, 1H), 7.6 (m, 2H), 7.8 (s, 1H), 10.9 (s, 1H).

b) 2-[(2-Bromophenoxy)methyl]-1-methylpiperidine

The title compound was made from (1-methylpiperidin-2-yl)methanol in asimilar manner to Example 126 (b).

MS (ES) 284 (M+H)⁺.

¹H NMR (CDCl₃) 1.4-2.0 (m, 6H), 2.1-2.2 (m, 1H), 2.35 (s, 3H), 2.55 (m,1H), 2.7-2.8 (m, 1H), 2.9-3.0 (m, 1H), 4.1-4.2 (m, 1H), 6.8-6.9 (m, 2H),7.2 (m, 1H), 7.5 (m, 1H).

Example 130(2S)-2-[(Aminocarbonyl)amino]-5-(2-{[1-methylpyrrolidin-2-yl]methoxy}phenyl)-3-thiophenecarboxamide

a) The title compound was made from(2S)-2-[(2-bromophenoxy)methyl]-1-methylpyrrolidine in a similar mannerto Example 43 (a) and the precipitate purified by preparative HPLC.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65-1.8 (m, 3H) 2.2 (m, 2H), 2.4 (s, 3H), 2.75 (m,1H), 3.0 (m, 1H), 3.85 (m, 1H), 4.2 (m, 1H), 6.8-6.9 (brs, 2H), 7.0 (t,1H), 7.1 (m, 1H), 7.2-7.3 (m, 2H), 7.5-7.7 (m, 2H), 7.8 (s, 1H), 10.9(s, 1H).

b) (2S)-2-[(2-Bromophenoxy)methyl]-1-methylpyrrolidine

The title compound was made from (S)-(−)-1-methyl-2-pyrrolidinemethanolin a manner similar to Example 126 (b).

MS (ES) 270 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65-1.8 (m, 3H), 2.2-2.3 (m, 2H), 2.4 (s, 3H), 2.65(m, 1H), 3.0 (m, 1H), 3.9-4.05 (m, 2H), 6.9 (m, 1H), 7.1-7.2 (m, 1H),7.35 (m, 1H), 7.55 (m, 1H).

Example 1312-[(Aminocarbonyl)amino]-5-(2-{[1-(2-methoxyethyl)pyrrolidin-3-yl]oxy}phenyl)-3-thiophenecarboxamide

a) The title compound was made from3-(2-bromophenoxy)-1-(2-methoxyethyl)-pyrrolidine in a similar manner toExample 43 (a). The precipitate was purified by cation exchangechromatography eluting with ammonia/methanol/dichloromethane mixtures.

MS (ES) 405 (M+H)⁺.

¹H NMR (DMSO-D6) 1.9-2.0 (m, 1H), 2.2-2.3 (m, 1H), 2.6-2.7 (m, 2H), 2.75(m, 2H), 3.1 (m, 1H), 3.2 (m, 1H), 3.25 (s, 3H), 3.45 (m, 2H), 4.95 (m,1H), 6.8-6.9 (brs, 2H), 6.95-7.05 (m, 2H), 7.25 (m, 2H), 7.6-7.7 (m,2H), 7.75 (s, 1H), 10.9 (s, 1H).

b) 3-(2-Bromophenoxy)-1-(2-methoxyethyl)pyrrolidine

3-(2-Bromophenoxy)pyrrolidine (1.23 g), 1-bromo-2-methoxyethane (0.526ml) and potassium carbonate (842 mg) were mixed with dimethylformamide(50 ml) and stirred for two days. The mixture was added to water (100ml). The mixture was extracted with diethyl ether (3×50 ml), washed withwater (2×50 ml), brine (2×30 ml), dried (MgSO₄) and concentrated invacuo. Purification was achieved using cation exchange chromatographyeluting with ammonia/methanol/dichloromethane mixtures yielding productas a clear oil (0.8 g).

MS (ES) 300 (M+H)⁺.

¹H NMR (DMSO-D6) 1.7-1.8 (m, 1H), 2.2-2.3 (m, 1H), 2.5-2.8 (m, 5H), 2.9(m, 1H), 3.2 (s, 3H), 3.4 (m, 2H), 4.9 (m, 1H), 6.90-6.95 (m, 1H), 7.0(m, 1H), 7.25-7.35 (m, 1H), 7.5 (s, 1H).

Example 132(2R)-2-[(Aminocarbonyl)amino]-5-(2-{[1-methylpyrrolidin-2-yl]methoxy}phenyl)-3-thiophenecarboxamide

a) The title compound was made from(2R)-2-[(2-bromophenoxy)methyl]-1-methylpyrrolidine in a similar mannerto Example 43 (a) and the precipitate purified by preparative LCMS.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.65-1.8 (m, 3H) 2.2 (m, 2H), 2.4 (s, 3H), 2.75 (m,1H), 3.0 (m, 1H), 3.85 (m, 1H), 4.2 (m, 1H), 6.8-6.95 (brs, 2H), 7.0 (t,1H), 7.1 (m, 1H), 7.2-7.3 (m, 2H), 7.6-7.7 (m, 2H), 7.8 (s, 1H), 10.9(s, 1H).

b) (2R)-2-[(2-Bromophenoxy)methyl]-1-methylpyrrolidine

(2R)-2-[(2-Bromophenoxy)methyl]pyrrolidine (1.84 g), potassium carbonate(1.09 g) and methyl iodide (0.49 ml) were stirred in dimethylformamide(10 ml) for 2 h at room temperature. The mixture was concentrated invacuo and water added (50 ml). The mixture was extracted with diethylether (3×30 ml). The organic portions were combined and washed withwater (2×20 ml), brine (2×20 ml) and dried (MgSO₄) and concentrated invacuo yielding the title compound as a pale orange oil (0.75 g).

MS (ES) 270 (M+H)⁺.

¹H NMR (DMSO-D6) 1.6-1.75 (m, 3H), 2.0 (m, 1H), 2.2 (m, 1H), 2.45 (s,3H), 2.8 (m, 1H), 2.95 (m, 1H), 3.8-4.05 (m, 2H) 6.8 (m, 1H), 7.1 (m,1H), 7.3 (m, 1H), 7.55 (m, 1H).

c) (2R)-2-[(2-Bromophenoxy)methyl]pyrrolidine

This compound was made from(2R)-1-tert-butyloxycarbonyl-2-(hydroxymethyl)pyrrolidine (2 g) in asimilar manner to Example 127 (b-c), yielding the product as a brown oil(1.84 g).

MS (ES) 256 (M+H)⁺.

¹H NMR (DMSO-D6) 1.5-1.9 (m, 4H), 2.8-2.9 (m, 2H), 3.45 (m, 1H),3.85-4.0 (m, 2H), 6.9 (m, 1H), 7.15 (m, 1H), 7.35 (m, 1H), 7.6 (m, 1H).

Example 1332-[(Aminocarbonyl)amino]-5-[2-(2-(2,2,6-tetramethylpiperidin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenoxy)ethyl]-2,2,6-trimethylpiperidine in a similarmanner to Example 9 (e).

MS (ES) 431 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (s, 3H), 1.0 (d, 3H), 1.05 (s, 3H), 1.4 (m, 6H),2.6 (m, 2H), 3.1 (m, 1H), 3.95 (m, 2H), 6.8 (brs, 2H), 6.95 (m, 1H),7.05 (dd, 1H), 7.2 (m, 2H), 7.6 (dd, 1H), 7.6 (brs, 1H), 7.75 (s, 1H),10.91 (brs, 1H).

b) 1-[2-(2-Bromophenoxy)ethyl]2,2,6-trimethylpiperidine

The title compound was prepared from1-(2-chloroethyl)-2,2,6-trimethylpiperidine hydrochloride and2-bromophenol in a similar manner to Example 2 (b).

MS (ES) 326 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (s, 3H), 1.0 (d, 3H), 1.05 (s, 3H), 1.4 (m, 6H),2.6 (m, 2H), 3.0 (m, 1H), 3.9 (m, 2H), 6.95 (m, 1H), 7.05 (dd, 1H), 7.3(m, 1H), 7.55 (dd, 1H).

c) 1-(2-Chloroethyl)-2,2,6-trimethylpiperidine

The title compound was prepared as described in GB Patent 831345.

Example 1342-[(Aminocarbonyl)amino]-5-{5-chloro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4-chlorophenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) except that the concentrated reaction mixture waspartitioned between dichloromethane and saturated sodium carbonatesolution. The solvent layer was washed (brine), dried and evaporated toan oil. The pure product was obtained by silica chromatography elutingwith dichloromethane/methanol mixtures.

MS (ES) 423 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.95 (m, 1H), 2.2 (m, 1H), 2.55 (m, 1H),2.7 (m, 1H), 2.8 (m, 2H), 3.1 (m, 1H), 4.95 (m, 1H), 6.8 (m, 2H), 6.95(dd, 1H), 7.15 (d, 1H), 7.2 (brs, 1H), 7.6 (brs, 1H), 7.68 (s, 1H), 7.8(s, 1H), 10.85 (s, 1H).

b) 3-(2-Bromo-4-chlorophenoxy)-1-isopropylpyrrolidine

Sodium hydride (0.43 g, 60% dispersion in oil) was added portionwise toa stirred solution of 2-bromo-4-chlorophenol (2.1 g) indimethylacetamide (15 ml). After stirring for 15 minutes, a solution of1-isopropylpyrrolidin-3-yl methanesulphonate (15 mmol) indimethylacetamide (15 ml) was added portionwise and the resultingmixture was heated at 90° C. for 18 h. The solvent was evaporated andthe residue dissolved in ethyl acetate/water. The solvent phase waswashed twice with brine and then dried and evaporated to an oil.Purification was achieved using silica chromatography eluting withdichloromethane/methanol mixtures. This gave the title compound (3.0 g).

MS (ES) 318 (M+H)⁺.

¹H NMR (DMSO-D6) 1.2 (d, 6H), 2.1 (m, 1H), 2.25 (m, 1H), 3.2 (m, 4H),3.6 (m, 1H), 5.15 (m, 1H), 7.2 (d, 1H), 7.4 (m, 1H), 7.7 (d, 1H).

c) 1-Isopropylpyrrolidin-3-yl methanesulphonate

A solution of 1-isopropylpyrrolidin-3-ol (2.0 ml) and triethylamine (2.5ml) in toluene (25 ml) was cooled to 0° C. and methanesulphonyl chloride(1.4 ml) was added dropwise with stirring. The mixture was allowed towarm to ambient temperature and stirred for a further 2 h. The reactionwas filtered and the filtrate evaporated to an oil which was usedimmediately.

Example 1352-[(Aminocarbonyl)amino]-5-{4-fluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-5-fluorophenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134(a).

MS (ES) 407 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.9 (m, 1H), 2.2 (m, 1H), 2.4 (m, 2H), 2.7(m, 2H), 3.05 (m, 1H), 4.95 (m, 1H), 6.8 (m, 3H), 7.2 (brs, 1H), 7.55(m, 2H), 7.65 (s, 1H), 7.8 (s, 1H), 10.88 (brs, 1H).

b) 3-(2-Bromo-5-fluorophenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-5-fluorophenol in a similarmanner to Example 134 (b).

MS (ES) 302 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.8 (m, 1H), 2.2 (m, 1H), 2.4 (m, 1H),2.65 (m, 2H), 3.0 (m, 2H), 4.9 (m, 1H), 6.75 (m, 1H), 6.95 (m, 1H), 7.6(m, 1H).

Example 1362-[(Aminocarbonyl)amino]-5-{4,5-difluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The tide compound was prepared from3-(2-bromo-4,5-difluorophenoxy)-1-isopropylpyrrolidine in a similarmanner to Example 9 (e)) and the purification was achieved as Example134 (a).

MS (ES) 425 (M+H)⁺.

¹H NMR (DMSO-D6) 1.05 (d, 6H), 2.0 (m, 1H), 2.25 (m, 1H), 2.4 (m, 1H),2.55 (m, 1H), 2.7 (m, 2H), 3.1 (m, 1H), 5.0 (m, 1H), 6.9 (brs, 2H), 7.2(m, 1H), 7.3 (brs, 1H), 7.55 (brs, 1H), 7.6 (m, 1H), 7.8 (s, 1H), 10.9(brs, 1H).

b) 3-(2-Bromo-4,5-difluorophenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4,5-difluorophenol in asimilar manner to Example 134 (b) except that the compound was purifiedby cation exchange chromatography eluting with ammonia/methanolmixtures.

MS (ES) 320 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.75 (m, 1H), 2.2 (m, 1H), 2.4 (m, 1H),2.65 (m, 2H), 2.95 (m, 2H), 4.85 (m, 1H), 7.25 (m, 1H), 7.8 (m, 1H).

Example 1372-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-methylphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4-methylphenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134 (a)except that cation exchange chromatography was employed usingmethanol/ammonia mixtures with final purification by preparative hplc.

MS (ES) 403 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.9 (m, 1H), 2.1 (m, 1H), 2.15 (s, 3H),2.4 (m, 1H), 2.55 (m, 1H), 2.7 (m, 2H), 3.0 (m, 1H), 4.9 (m, 1H), 6.8(brs, 2H), 6.85 (d, 1H), 6.95 (m, 1H), 7.2 (brs, 1H), 7.4 (s, 1H), 7.6(brs, 1H), 7.7 (s, 1H), 10.89 (brs, 1H).

b) 3-(2-Bromo-4-methylphenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4-methylphenol in a similarmanner to Example 134 (b) except that the compound was purified bycation exchange chromatography eluting with ammonia/methanol mixtures.

MS (ES) 298 (M+H)⁺.

Example 1382-[(Aminocarbonyl)amino]-5-{5-cyano-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4-cyanophenoxy)-1-isopropylpyrrolidine in a similar manner toExample 9 (e) and the purification was achieved in as in Example 134 (a)except that cation exchange chromatography was employed usingmethanol/ammonia mixtures with final purification by preparative hplc.

MS (ES) 414 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.95 (m, 1H), 2.15 (m, 1H), 2.6 (m, 1H),2.8 (m, 2H), 3.1 (m, 2H), 5.1 (m, 1H), 6.8 (brs, 2H), 7.15 (d, 1H), 7.25(brs, 1H), 7.6 (brs, 1H), 7.65 (d, 1H), 7.85 (s, 1H), 8.0 (s, 1H), 10.9(brs, 1H).

b) 3-(2-Bromo-4-cyanophenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4-cyanophenol in a similarmanner to Example 134 (b) except that the compound was purified bycation exchange chromatography eluting with ammonia/methanol mixtures.

MS (ES) 309 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.8 (m, 1H), 2.2 (m, 2H), 2.6 (m, 1H),2.65 (m, 2H), 2.95 (m, 1H), 5.0 (m, 1H), 7.2 (d, 1H), 7.8 (m, 1H), 8.1((m, 1M).

Example 1392-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-methoxyphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4-methoxyphenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134 (a)except that the crude product was purified by trituration withdichloromethane/methanol mixtures.

MS (ES) 419 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.9 (m, 1H), 2.15 (m, 1H), 2.4 (m, 1H),2.55 (m, 1H), 2.7 (m, 2H), 3.0 (m, 1H), 3.75 (s, 3H), 4.8 (m, 1H), 6.75(m, 1H), 6.8 (brs, 2H), 6.9 (m, 1H), 7.2 (m, 1H), 7.22 (brs, 1H), 7.6(brs, 1H), 7.8 (s, 1H), 10.85 (brs, 1H).

b) 3-(2-Bromo-4-methoxyphenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4-methoxyphenol in asimilar manner to Example 134 (b) except that the compound was purifiedby cation exchange chromatography eluting with ammonia/methanolmixtures.

MS (ES) 314 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.9 (m, 2H), 2.4 (m, 1H), (2.5, 1Hobscured), 2.75 (m, 3H), 3.8 (s, 3H), 4.8 (m, 1H), 6.7 (m, 1H), 6.9 (m,1H), 7.2 (m, 1H).

c) 2-Bromo-4-methoxyphenol

The title compound was prepared as described in S. Afr. J. Chem., 1999,52, 112.

Example 1402-[(Aminocarbonyl)amino]-5-{3,5-difluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4,6-difluorophenoxy)-1-isopropylpyrrolidine in a similarmanner to Example 9 (e) and the purification was achieved as in Example134 (a) except that the compound was purified by cation exchangechromatography eluting with ammonia/methanol mixtures and subsequentpreparative hplc.

MS (ES) 425 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (m, 6H), 1.95 (m, 2H), 2.4 (m, 1H), 2.75 (m, 4H),4.7 (m, 1H), 6.9 (m, 2H), 7.2 (m, 2H), 7.4 (m, 1H), 7.6 (m, 1H), 7.85(s, 1H), 10.95 (brs, 1H).

b) 3-(2-Bromo-4,6-difluorophenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4,6-difluorophenol in asimilar manner to Example 134 (b) except that the compound was purifiedby cation exchange chromatography eluting with ammonia/methanol mixturesand subsequent preparative hplc.

MS (ES) 320 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.95 (m, 1H), 2.05 (m, 1H), 2.4 (m, 1H),(2.5, 1H), obscured), 2.8 (m, 3H), 4.7 (m, 1H), 7.4 (m, 2H).

Example 1412-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-3-methoxyphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-6-methoxyphenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134 (a)except that the compound was purified by cation exchange chromatographyeluting with ammonia/methanol mixtures and subsequent preparative hplc.

MS (ES) 419 (M+H)⁺.

¹H NMR (DMSO-D6) 0.95 (d, 6H), 1.8 (m, 2H), 2.4 (m, 2H), 2.8 (m, 3H),3.8 (s, 3H), 4.8 (m, 1H), 6.8 (m, 2H), 6.9 (m, 1H), 7.1 (m, 2H), 7.2 (m,1H), 7.55 (brs, 1H), 7.7 (s, 1H), 10.92 (brs, 1H).

b) 3-(2-Bromo-6-methoxyphenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-6-methoxyphenol in asimilar manner to Example 134 (b) except that the compound was purifiedby cation exchange chromatography eluting with ammonia/methanolmixtures.

MS (ES) 314 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.95 (m, 2H), 2.4 (m, 1H), (2.5, 1Hobscured), 2.75 (m, 3H), 3.8 (s, 3H), 4.8 (m, 1H), 7.0 (m, 2H), 7.15 (m,1H).

c) 2-Bromo-6-methoxyphenol

The title compound was prepared as described in Synthesis, 2001, 741.

Example 1422-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-5-trifluoromethylphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-[2-bromo-4-trifluoromethylphenoxy]-1-isopropylpyrrolidine in a similarmanner to Example 9 (e) and the purification was achieved as in Example134 (a) except that the compound was obtained pure by washing withmethanol.

MS (ES) 457 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.95 (m, 1H), 2.25 (m, 2H), 2.55 (m, 1H),2.8 (m, 2H), 3.1 (m, 1H), 5.05 (m, 1H), 6.8 (m, 2H), 7.2 (m, 1H), 7.25(m, 1H), 7.5 (m, 1H), 7.65 (m, 1H), 7.9 (m, 2H) 10.92 (m, 1H).

b) 3-[2-Bromo-4-trifluoromethylphenoxy]-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-4-trifluoromethylphenol ina similar manner to Example 134 (b) except that the compound waspurified by cation exchange chromatography eluting with ammonia/methanolmixtures.

MS (ES) 352 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.8 (m, 1H), 2.2-2.4 (m, 3H), 2.7 (m, 2H),3.0 (m, 1H), 5.0 (m, 1H), 7.2 (d, 1H), 7.65 (m, 1H), 7.9 (d, 1H).

c) 2-Bromo-4-trifluoromethylphenol

The title compound was prepared as described in Chem. Pharm. Bull, 1996,44, 4.

Example 1432-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-4-trifluoromethylphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-[2-bromo-5-trifluoromethylphenoxy]-1-isopropylpyrrolidine in a similarmanner to Example 9 (e) and the purification was achieved as in Example134 (a) except that the compound was obtained pure by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 457 (M+H)⁺.

¹H NMR (DMSO-D6) 1.05 (d, 6H), 2.0 (m, 1H), 2.3 (m, 1H), 2.5 (m, 2H),2.8 (m, 2H), 3.1 (m, 1H), 5.1 (m, 1H), 6.9 (m, 2H), 7.3 (m, 2H), 7.6 (m,2H), 7.9 (dd, 1H), 8.0 (s, 1H), 10.95 (s, 1H).

b) 3-[2-Bromo-5-trifluoromethylphenoxy]-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-5-trifluoromethylphenol ina similar manner to Example 134 (b) except that the compound waspurified by cation exchange) chromatography eluting withammonia/methanol mixtures.

MS (ES) 352 (M+H)⁺.

¹H NMR (CDCl₃) 1.05 (d, 6H), 2.0 (m, 1H), 2.3 (m, 1H), 2.5 (m, 1H), 2.8(m, 3H), 3.2 (m, 1H), 4.85 (m, 1H), 7.0 (d, 1H), 7.05 (d, 1H), 7.4 (d,1H).

c) 2-Bromo-5-(trifluoromethyl)phenol

The title compound was prepared as described in Chem. Pharm. Bull.,1996, 44, 4.

Example 1442-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-4-methoxyphenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-5-methoxyphenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134 (a)except that the compound was obtained pure by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 419 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.9 (m, 1H), 2.2 (m, 1H), 2.4 (m, 1H),2.55 (m, 1H), 2.7 (m, 2H), 3.0 (m, 1H), 3.75 (s, 3H), 4.95 (m, 1H), 6.5(m, 1H), 6.6 (m, 1H), 6.8 (brs, 2H), 6.9 (m, 1H), 7.2 (brs, 1H), 7.5 (m,1H), 7.55 (s, 1H), 10.86 (brs, 1H).

b) 3-(2-Bromo-5-methoxyphenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-5-methoxyphenol in asimilar manner to Example 134 (b) except that the compound was purifiedby cation exchange chromatography eluting with ammonia/methanolmixtures.

MS (ES) 314 (M+H)⁺.

¹H NMR (CDCl₃) 1.1 (d, 6H), 2.0 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1H),2.75 (m, 3H), 3.2 (m, 1H), 3.75 (s, 3H), 4.8 (m, 1H), 6.4 (m, 2H), 7.4(m, 1H).

c) 2-Bromo-5-methoxyphenol

The title compound was prepared as described in J. Chem. Soc. PerkinTrans 1; 12, 2927 (1983).

Example 1452-[(Aminocarbonyl)amino]-5-{5-fluoro-2-[(1-isopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromo-4-fluorophenoxy)-1-isopropylpyrrolidine in a similar mannerto Example 9 (e) and the purification was achieved as in Example 134 (a)except that the compound was obtained pure by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 407 (M+H)⁺.

¹H NMR-(DMSO-D6) 1.0 (d, 6H), 1.95 (m, 1H), 2.2 (m, 1H), 2.4 (m, 1H),2.6 (m, 1H), 2.75 (m, 2H), 3.05 (m, 1H), 4.95 (m, 1H), 6.8 (m, 2H), 7.0(m, 2H), 7.2 (brs, 1H), 7.4 (m, 1H), 7.6 (brs, 1H), 7.8 (s, 1H), 10.88(brs, 1H).

b) 3-(2-Bromo-4-fluorophenoxy)-1-isopropylpyrrolidine

The title compound was prepared from 2-bromo-5-fluorophenol in a similarmanner to Example 134 (b) except that the compound was purified bycation exchange chromatography eluting with ammonia/methanol mixtures.

MS (ES) 302 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (d, 6H), 1.8 (m, 1H), 2.2 (m, 1H), 2.35 (m, 1H),2.5 (m, 1H), 2.6 (m, 2H), 2.95 (m, 1H), 4.8 (m, 1H), 7.0 (m, 1H), 7.2(m, 1H), 7.5 (m, 1H).

Example 1462-[(Aminocarbonyl)amino]-5-{2-[(1-isopropylpyrrolidin-3-yl)oxy]-3-(morpholin-4-ylmethyl)phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-{3-bromo-2-[(1-isopropylpyrrolidin-3-yl)oxy]benzyl}morpholine in asimilar manner to Example 9 (e) and the purification was achieved as inExample 134 (a) except that the compound was initially purified bycation exchange chromatography eluting with ammonia/methanol mixtures.Final purification was achieved using preparative hplc.

MS (ES) 488 (M+H)⁺.

¹H NMR (DMSO-D6) 2.0 (m, 1H), 2.3 (m, 1H), 2.55 (m, 2H), 2.75 (m, 2H),3.0 (m, 1H), 3.7 (m, 2H)) 5.0 (m, 1H), 6.8 (brs, 2H), 6.95 (m, 2H), 7.1(m, 2H), 7.2 (brs, 1H), 7.3 (m, 2H), 7.6 (m, 2H), 7.8 (s, 1H), 10.95 (s,1H).

b) 4-{3-Bromo-2-[(1-isopropylpyrrolidin-3-yl)oxy]benzyl}morpholine

The title compound was prepared from2-bromo-6-(morpholin-4-ylmethyl)phenol in a similar manner to Example134 (b) except that the compound was purified by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 383 (M+H)⁺.

¹H NMR (CDCl₃) 1.1 (m, 6H), 2.15 (m, 2H), 2.5 (m, 4H), 2.6 (m, 1H), 2.9(m, 4H), 3.6 (d, 2H), 3.7 (m, 4H), 4.9 (m, 1H), 6.95 (m, 1H), 7.35 (dd,1H), 7.45 (dd, 1H).

c) 2-Bromo-6-(morpholin-4-ylmethyl)phenol

Sodium triacetoxyborohydride (3.18 g) was added to a solution of3-bromo-2-hydroxybenzaldehyde (2.0 g) and morpholine (1.04 ml) intetrahydrofuran (30 ml) and the mixture stirred at ambient temperaturefor 18 h. After filtering from a little insoluble material, the filtratewas evaporated. The residue was partitioned between dichloromethane andwater and the solvent phase was washed with water, dried and evaporatedto an oil.

MS (ES) 272 (M+H)⁺.

¹H NMR (CDCl₃) 2.6 (m, 4H), 3.7 (s, 2H), 3.8 (m, 4H), 6.75 (m, 1H), 6.9(m, 1H), 7.4 (m, 1H).

Example 1472-[(Aminocarbonyl)amino]-5-(2-{[(1-(cyclopropylmethyl)pyrrolidin-3-yl]oxy}phenyl)-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromophenoxy)-1-(cyclopropylmethyl)-pyrrolidine in a similar mannerto Example 134 (a) except that the compound was purified by cationexchange chromatography eluting with ammonia/methanol mixtures.

MS (ES) 401 (M+H)⁺.

¹H NMR (DMSO-D6) 0.05 (m, 2H), 0.4 (m, 2H), 0.8 (m, 1H), 1.7 (m, 1H),1.9 (m, 1H), 2.2 (m, 2H), 2.55 (m, 1H), 2.6 (m, 2H), 3.0 (m, 1H), 4.9(m, 1H), 6.8 (m, 2H), 6.9 (m, 2H), 7.15 (m, 2H), 7.2 (brs, 1H), 7.55 (m,1H), 7.65 (s, 1H), 10.84 (s, 1H).

b) 3-(2-Bromophenoxy)-1-(cyclopropylmethyl)pyrrolidine

The title compound was prepared from 2-bromophenol and1-(cyclopropylmethyl)pyrrolidin-3-yl methanesulphonate in a similarmanner to Example 134 (b) except that the compound was purified bycation exchange chromatography eluting with ammonia/methanol mixtures.

MS (ES) 296 (M+H)⁺.

¹H NMR (CDCl₃) 0.15 (m, 2H), 0.5 (m, 2H), 0.9 (m, 1H), 2.4 (m, 2H), 2.8(m, 3H), 3.0 (d, 2H), 3.2 (m, 1H), 4.9 (m, 1H), 6.8 (m, 2H), 7.2 (m,1H), 7.5 (m, 1H).

c) 1-(Cyclopropylmethyl)pyrrolidin-3-yl-methanesulphonate

The title compound was prepared in a similar manner to Example 134 (c)except that 1-(cyclopropylmethyl)pyrrolidin-3-ol was used.

d) 1-(Cyclopropylmethyl)pyrrolidin-3-ol

The title compound was prepared in a similar manner to Bull. Chem. Soc.Japan, 69, 213 (1996) except that cyclopropanemethyl bromide was used.

MS (ES) 142 (M+H)⁺.

Example 1482-[(Aminocarbonyl)amino]-S-{2-[(1-cyclopropylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromophenoxy)-1-cyclopropylpyrrolidine in a similar manner toExample 9 (e) and the purification, was achieved as in Example 134 (a)except that the product was isolated from the dichloromethane extract bycation exchange chromatography eluting with ammonia/methanol mixtures.Final purification was achieved using preparative hplc.

MS (ES) 387 (M+H)⁺.

¹H NMR (DMSO-D6) 0.3 (m, 3H), 0.8 (m, 1H), 1.4 (m, 1H), 1.65 (m, 1H),1.9 (m, 1H), 2.2 (m, 1H), 2.3 (m, 1H), 2.65 (m, 1H), 2.9 (m, 1H), 4.95(m, 1H), 6.9 (m, 2H), 7.0 (m, 2H), 7.2 (m, 2H), 7.6 (m, 2H), 7.7 (s,1H), 10.9 (s, 1H).

b) 3-(2-Bromophenoxy)-1-cyclopropylpyrrolidine

The title compound was prepared from 2-bromophenol and1-cyclopropylpyrrolidin-3-yl methanesulphonate in a similar manner toExample 134 (b) except that the compound was purified by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 282 (M+H)⁺.

¹H NMR (CDCl₃) 0.6 (m, 2H), 0.95 (m, 3H), 1.6 (m, 1H), 2.0 (m, 1H), 2.2(m, 1H), 2.7 (m, 1H), 2.9 (m, 1H), 3.2 (m, 1H), 4.8 (m, 1H), 6.8 (m,2H), 7.2 (m, 1H), 7.55 (m, 1H).

c) 1-Cyclopropylpyrrolidin-3-yl methanesulphonate

The title compound was prepared in a similar manner to Example 134 (c)except that 1-cyclopropylpyrrolidin-3-ol was used.

d) 1-Cyclopropylpyrrolidin-3-ol

The title compound was prepared in a similar manner to J. Med. Pharm.Chem., 1, 73 (1959) except that cyclopropylamine was used.

MS (ES) 128 (M+H)⁺.

¹H NMR (CDCl₃) 0.4 (m, 2H), 0.95 (m, 3H), 1.65 (m, 2H), 2.0 (br, 1H),2.2 (m, 2H), 2.5 (m, 1H), 2.9 (m, 1H), 4.35 (m, 1H).

Example 1492-[(Aminocarbonyl)amino]-5-{2-[(2-(4-fluoropiperidin-1-yl)ethoxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenoxy)ethyl]-4-fluoropiperidine in a similar manner toExample 9 (e) and the purification was achieved as in Example 134 (a)except that the product was isolated from the dichloromethane phaseusing cation exchange chromatography eluting with ammonia/methanolmixtures. Final purification was achieved using preparative hplc.

MS (ES) 407 (M+H)⁺.

¹H NMR (DMSO-D6) 1.8 (m, 2H), 2.0 (m, 1H), 2.4 (m, 2H), 2.6 (m, 2H), 3.0(m, 1H), 4.0 (m, 1H), 4.2 (m, 2H), 4.6 (m, 1H), 5.6 (m, 1H), 6.8 (brs,2H), 6.95 (m, 1H), 7.05 (m, 1H), 7.2 (m, 2H), 7.6 (m, 2H), 7.75 (d, 1H),10.9 (brs, 1H).

b) 1-[2-(2-Bromophenoxy)ethyl]-4-fluoropiperidine

A mixture of 1-bromo-2-(2-chloroethoxy)benzene (2.35 g),4-fluoropiperidine hydrochloride (1.54 g), potassium carbonate (4.06 g)and potassium iodide (0.83 g) in dimethylformamide (20 ml) was heated at80° C. for 18 h. After evaporation, the residue was partitioned betweenethyl acetate and water. The solvent phase was washed (brine), dried andevaporated to give an oil (1.0 g).

MS (ES) 302 (M+H)⁺.

¹H NMR (CDCl₃) 1.9 (m, 2H), 2.2 (m, 2H), 2.8 (m, 2H), 2.9 (m, 1H), 2.95(m, 1H), 4.2 (m, 2H), 4.7 (m, 2H), 5.75 (m, 1H), 6.8 (m, 2H), 7.2 (m,1H), 7.55 (m, 1H).

Example 1502-[(Aminocarbonyl)amino]-5-{2-[(1-methylpiperidin-4-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from4-(2-bromophenoxy)-1-methylpiperidine in a similar manner to Example 9(e) except that the pure product was obtained by triturating the crudesolid with a dichloromethane/methanol mixture.

MS (ES) 375 (M+H)⁺.

¹H NMR (DMSO-D6) 1.85 (m, 2H), 2.05 (m, 4H), 2.8 (s, 3H), 3.1 (m, 2H),4.6 (m, 1H), 6.8 (m, 3H), 7.2 (m, 3H), 7.65 (m, 2H), 7.8 (s, 1H), 10.94(brs, 1H).

b) 4-(2-Bromophenoxy)-1-methylpiperidine

The title compound was prepared from 2-bromophenol and1-methylpiperidin-4-yl methanesulphonate in a similar manner to Example134 (b) except that the compound was purified by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 270 (M+H)⁺.

c) 1-Methylpiperidin-4-yl methanesulphonate

The title compound was prepared in a similar manner to Example 134 (c)except that 1-methylpiperidin-4-ol was used.

Example 1512-[(Aminocarbonyl)amino]-5-{2-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide

a) The title compound was prepared from3-(2-bromophenoxy)-1-methylpyrrolidine in a similar manner to Example 9(e) except that the pure product was obtained by triturating the crudesolid with a dichloromethane/methanol mixture.

MS (ES) 361 (M+H)⁺.

¹H NMR (DMSO-D6) 1.95 (m, 1H), 2.2 (m, 1H), 2.25 (s, 3H), 2.45 (m, 1H),2.65 (m, 2H), 2.9 (m, 1H), 5.0 (m, 1H), 6.8 (brs, 2H), 6.95 (m, 2H), 7.2(m, 2H), 7.6 (dd, 2H), 7.8 (s, 1H), 10.9 (brs, 1H).

b) 3-(2-Bromophenoxy)-1-methylpyrrolidine

The title compound was prepared from 2-bromophenol and1-methylpyrrolidin-3-yl methanesulphonate in a similar manner to Example134 (b) except that the compound was purified by cation exchangechromatography eluting with ammonia/methanol mixtures.

MS (ES) 256 (M+H)⁺.

¹H NMR(CDCl₃) 2.0 (m, 1H), 2.3 (m, 1H), 2.4 (s, 3H), 2.6 (m, 1H), 2.75(m, 2H), 3.0 (m, 1H), 4.8 (m, 1H), 6.8 (m, 2H), 7.2 (m, 1H), 7.55 (m,1H).

c) 1-Methylpyrrolidin-3-yl methanesulphonate

The title compound was prepared in a similar manner to Example 134 (c)except that 1-methylpyrrolidin-3-ol was used.

Example 1522-[(Aminocarbonyl)amino]-5-[4-(2-{morpholin-4-yl}acetyl)phenyl]3-thiophenecarboxamide

a) The title compound was prepared from1-(4-bromophenyl)-2-(morpholin-4-yl)ethanone in a similar manner toExample 9 (e).

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 2.55 (m, 4H), 3.6 (m, 4H), 3.8 (s, 2H), 6.8 (brs, 1H),7.0 (brs, 2H), 7.35 (brs, 1H), 7.6 (d, 2H), 7.9 (s, 1H), 8.0 (d, 2H),11.06 (s, 1H).

b) 1-(4-Bromophenyl)-2-(morpholin-4-yl)ethanone

Morpholine (4.35 g) in dry toluene (8 ml) was stirred during theaddition of aliquots of 2-bromo-1-(4-bromophenyl)ethanone (6.95 g) indry toluene (70 ml). The resulting precipitate was removed by filtrationand the filtrate evaporated to give the product (J. Amer. Chem. Soc.,1940, 62, 2882) as a pale yellow solid (7.2 g).

MS (ES) 284 (M+H)⁺.

¹H NMR (CDCl₃) 2.61 (m, 4H), 3.78 (m, 6H), 7.61 (dd, 2H), 7.90 (dd, 2H).

Example 1532-[(Aminocarbonyl)amino]-5-[2-{2-(4-hydroxy-1-piperidinyl)ethoxy}phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenoxy)ethyl]-4-piperidinol in a similar manner to Example38. Purification by cation exchange chromatography eluting withammonia/methanol mixtures gave the product (320 mg).

MS (ES) 405 (M+H)⁺.

¹H NMR (DMSO-D6) 1.35 (m, 2H), 1.6 (m, 2H), 2.15 (m, 2H), 2.8 (m, 4H),3.4 (m, 1H), 4.2 (t, 2H), 6.8 (brs, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 7.2(m, 2H), 7.6 (m, 2H), 7.8 (s, 1H), 11.0 (s, 1H).

b) 1-[2-(2-Bromophenoxy)ethyl]-4-piperidinol

The title compound was prepared from 1-bromo-2-(2-chloroethoxy)benzeneand 4-hydroxypiperidine in a similar manner to Example 149 (b).

MS (ES) 300 (M+H)⁺.

¹H NMR (CDCl₃) 1.6 (m, 2H), 1.75 (brs, 1H), 1.9 (m, 2H), 2.4 (m, 2H),2.9 (m, 4H), 3.7 (m, 1H), 4.15 (m, 2H), 6.8 (m, 2H), 7.2 (m, 1H), 7.55(m, 1H).

Example 1542-[(Aminocarbonyl)amino]-5-[2-(2-(2,2,6,6-tetramethylpieridin-1-yl)ethoxy)phenyl]-3-thiophenecarboxamide

a) The title compound was prepared from1-[2-(2-bromophenoxy)ethyl]-2,2,6,6-tetramethylpiperidine in a similarmanner to Example 9 (e).

MS (ES) 445 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (s, 12H), 1.35 (m, 4H), 1.5 (m, 2H), 3.0 (t, 2H),3.95 (t, 2H), 6.9 (brs, 2H), 7.0 (m, 1H), 7.3 (m, 2H), 7.4 (s, 1H), 7.6(m, 2H), 7.8 (m, 1H), 10.95 (brs, 1H).

b) 1-[2-(2-Bromophenoxy)ethyl]2,2,6-tetramethylpiperidine

The title compound was prepared from1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride and2-bromophenol in a similar manner to Example 2 (b).

MS (ES) 340 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0 (s, 12H), 1.3 (m, 4H), 1.5 (m, 2H), 2.8 (m, 2H),3.9 (m, 2H), 6.85 (m, 1H), 7.1 (dd, 1H), 7.3 (m, 1H), 7.55 (dd, 1H).

c) 1-(2-Chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride

The title compound was prepared as described in J. Med. Chem., 1963, 6,681.

Example 1552-[(Aminocarbonyl)amino]-5-{2-[2-(3-pyrrolin-1-yl)ethoxy]phenyl}thiophene-3-carboxamide

a) The title compound was prepared in a similar manner to Example 9 (e)but using 1-[2-(2-bromophenoxy)ethyl]-3-pyrroline.

MS (ES) 373 (M+H)⁺.

¹H NMR (DMSO-D6) 3.1 (t, 2H), 3.5 (s, 4H), 4.2 (t, 2H), 5.8 (s, 2H), 6.9(s, 2H), 7.0 (t, 1H), 7.15 (d, 1H), 7.2 (m, 2H), 7.6 (m, 2H), 7.8 (s,1H), 10.9 (s, 1H).

b) 1-[2-(2-Bromophenoxy)ethyl]-3-pyrroline

The title compound was prepared from 3-pyrroline and2-(2-bromophenoxy)ethyl chloride in a similar manner to Example 42 (b).

MS (ES) 268 (M+H)⁺.

¹H NMR (CDCl₃) 3.15 (t, 2H) 3.6 s, (4H), 4.2 (t, 2H), 5.8 (s, 2H), 6.8(t, 1H), 6.9 (d, 1H), 7.25 (m, 1H), 7.5 (m, 1H).

Example 156Cis/trans-2-[(Aminocarbonyl)amino]-5-{2-[2-(2,5-dimethyl-3-pyrrolin-1-yl)ethoxy]phenylthiophene-3-carboxamide

a) The title compound was prepared fromcis/trans-1-[2-(2-bromophenoxy)ethyl]-2,5-dimethyl-3-pyrroline in asimilar manner to Example 9 (e); the product was purified bychromatography on silica using methanol-dichloromethane mixtures.

MS (ES) 401 (M+H)⁺.

¹H NMR (DMSO-D6) 1.0-1.1 (m, 6H), 3.15 (m, 2H), 3.7, 3.85 (m, m, 2H),4.05-4.2 (m, 2H), 5.55, 5.7 (s, s, 2H), 6.8 (s, 2H), 7.0 (t, 1H), 7.15(d, 1H), 7.25 (m, 2H), 7.6 (m, 2H), 7.7 (s, 1H), 10.9 (s, 1H).

b) cis/trans-1-[2-(2-Bromophenoxy)ethyl]-2,5-dimethyl-3-pyrroline

The title compound was prepared from cis/trans-2,5-dimethyl-3-pyrrolineand 2-(2-bromophenoxy)ethyl chloride in a similar manner to Example 42(b); the product was purified by chromatography on silica usingmethanolic ammonia/dichloromethane mixtures.

MS (ES) 296 (M+H)⁺.

¹H NMR (CDCl₃) 1.1-1.2 (m, 6H), 2.9-3.3 (m, 2H), 3.8, 4.0 (m, m, 2H),4.15, (m, 2H), 5.65, 5.85 (s, s, 2H), 6.8 (t, 1H), 6.9 (d, 1H), 7.25 (m,1H), 7.5 (m, 1H).

Example 157(2S)-2-[(Aminocarbonyl)amino]-5-[4-(2-methoxymethyl-pyrrolidin-1-ylmethyl)phenyl]thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 103 (b)but starting from (2S)-2-methoxymethylpyrrolidine.

MS ES 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.55 (m, 1H), 1.65 (m, 2H), 1.90 (m, 1H), 2.15 (m, 1H),2.75 (m, 1H), 2.85 (m, 1H), 3.20-3.45 (m, 6H), 4.10 (m, 1H), 6.90 (s,2H), 7.30 (m, 3H), 7.50 (d, 2H), 7.65 (m, 2H), 10.95 (s, 1H).

Example 1582-[(Aminocarbonyl)amino]-5-[4-(4-aminocarbonylpiperidin-1-ylmethyl)phenylthiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 103 (b)but starting from 4-carboxamidopiperidine.

MS ES 402 (M+H)⁺.

¹H NMR (DMSO-D6) 1.55 (n, 2H), 1.65 (m, 2H), 1.90 (m, 2H), 2.05 (m, 1H),2.80 (m, 2H), 3.40 (s, 2H), 6.70 (s, 1H), 6.95 (s, 2H), 7.20 (s, 1H),7.30 (m, 3H), 7.45 (d, 2H), 7.65 (m, 2H), 11.00 (s, 1H).

Example 1592-[(Aminocarbonyl)amino]-5-[4-(3-hydroxymethylpiperidin-1-ylmethyl)phenyl]thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 106 butusing 3-hydroxymethylpiperidine

MS (ES) 389 (M+H)⁺.

¹H NMR (DMSO-D6) 0.90 (m, 1H), 1.45 (m, 1H), 1.60 (m, 4H), 1.90 (m, 1H),2.70 (m, 1H), 2.85 (m, 1H), 3.20 (m, 2H), 3.40 (m, 2H), 4.35 (s, 1H),6.90 (s, 2H), 7.30 (m, 3H), 7.45 (d, 2H), 7.70 (m, 2H), 11.00 (s, 1H).

Example 1602-[(Aminocarbonyl)amino]-5-[4-(4-hydroxymethylpiperidin-1-ylethyl)phenyl]thiophene-3-carboxamide

The title compound was prepared in a similar manner to Example 106 butusing 4-hydroxymethylpiperidine.

MS ES 389 (M+H)⁺.

¹H NMR (DMSO-D6) 1.15 (m, 2H), 1.35 (m, 1H), 1.60 (m, 2H), 1.85 (m, 2H),2.80 (m, 2H), 3.20 (m, 2H), 3.40 (s, 2H), 4.35 (t, 1H), 6.90 (s, 2H),7.30 (m, 3H), 7.45 (d, 2H), 7.65 (m, 2H), 10.95 (s, 1H).

Example 1612-[(Aminocarbonyl)amino]-5-[2-(3-{morpholin-4-yl}pyrrolidin-1-yl)phenyl]thiophene-3-carboxamide

a) The title compound was prepared from4-[1-(2-bromophenyl)pyrrolidin-3-yl]morpholine in a similar manner toExample 9 (e), except that on work-up the reaction mixture wasevaporated and the residue sonicated in dichloromethane and aqueoussodium hydrogen carbonate solution. The solvents were decanted off andthe residual black gum was dissolved in methanol and purified by cationexchange chromatography, eluting with 0-5% methanol in dichloromethane,then 2-5% ammonia solution (7M in methanol) in dichloromethane.Fractions containing product were evaporated, the residue was trituratedwith ether and the solid product collected by filtration.

MS (ES) 416 (M+H)⁺.

¹H NMR (DMSO-D6) 1.66-1.77 (m, 1H), 1.93-2.03 (m, 1H), 2.27-2.48 (m,4H), 2.83-3.15 (m, 5H), 3.48-3.62 (m, 4H), 6.83 (brs, 2H), 6.91 (td,1H), 7.02 (dd, 1H), 7.15-7.23 (n, 2H), 7.30 (dd, 1H), 7.40 (s, 1H), 7.59(brs, 1H), 10.95 (s, 1H).

b) 4-[1-(2-Bromophenyl)pyrrolidin-3-yl]morpholine

1-(2-Bromophenyl)pyrrolidin-3-ol (1 g) was stirred in toluene (30 ml).Triethylamine (0.69 ml) was added and the solution was cooled in anice-bath. Methane sulphonyl chloride (0.38 ml) was added dropwise. Thereaction mixture was allowed to warm to room temperature over 2 h andstirred for a further 2.5 h. The mixture was filtered, washed throughwith toluene and the filtrate concentrated to ca. 20 ml in vacuo.Morpholine (10 ml) was then added and the solution stirred at roomtemperature overnight, a further portion of morpholine (10 ml) was addedand the solution was heated at reflux for 24 h. Volatile materials werethen removed in vacuo, the residue was diluted with water (40 ml) andextracted with diethyl ether (3×20 ml). The combined extracts werewashed with brine, dried (MgSO₄), filtered and evaporated. The residuewas triturated with isohexane/diethyl ether and product collected byfiltration as a yellow solid (0.93 g).

MS (ES) 311 (M+H)⁺.

¹H NMR(CDCl₃) 1.80-1.95 (m, 1H), 2.10-2.25 (m, 1H), 2.45-2.65 (m, 4H),2.90-3.05 (m, 1H), 3.18-3.30 (m, 1H), 3.34-3.50 (m, 2H), 3.53-3.66 (m,1H), 3.70-3.82 (m, 4H), 6.77 (td, 1H), 6.92 (dd, 1H), 7.20 (td, 1H),7.50 (dd, 1H).

c) 1-(2-Bromophenyl)pyrrolidin-3-ol

2-Bromoaniline (2 g) was heated with 1,4-dibromo-2-butanol (1.58 ml) anddiisopropylethylamine (4.9 ml) in toluene (10 ml) at reflux for 20 h.The reaction mixture was allowed to cool, diluted with water (60 ml) andthe aqueous phase extracted with ethyl acetate (3×30 ml). The combinedextracts were washed with water, brine, dried (MgSO₄), filtered andevaporated. The residue was adsorbed onto silica and purified by columnchromatography, eluting with a gradient of 0-20% ethyl acetate inisohexane, to afford the product as a yellow oil (2.30 g).

MS (ES) 242 (M+H)⁺.

¹H NMR (CDCl₃) 1.89 (d, 1H), 1.91-2.04 (m, 1H), 2.15-2.28 (m, 1H),3.10-3.21 (m, 1H), 3.29-3.36 (m, 1H), 3.50-3.57 (m, 1H), 3.62-3.73 (m,1H), 4.46-4.55 (m, 1H), 6.80 (td, 1H), 6.95 (dd, 1H), 7.21 (td, 1H),7.51 (dd, 1H).

Example 1622-[(Aminocarbonyl)amino]-5-{2-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}thiophene-3-carboxamide

a) The title compound was prepared from1-(2-bromophenyl)-4-(2-methoxyethyl)-piperazine in a similar manner toExample 9 (e), except that on work-up the reaction mixture wasevaporated and the residue sonicated in dichloromethane and aqueoussodium hydrogen carbonate solution. The layers were separated and theaqueous phase extracted with a further portion of dichloromethane. Thecombined organic extracts were evaporated and purified by cationexchange chromatography, eluting with 0-8% methanol in dichloromethane,then 2-6% ammonia solution (7M in methanol) in dichloromethane.Fractions containing product were evaporated, the residue was trituratedwith a mixture of methanol and diethyl ether and the solid-productcollected by filtration.

MS (ES) 404 (M+H)⁺.

¹H NMR (DMSO-D6) 2.45-2.54 (m, 2H, partially obscured), 2.58-2.68 (m,4H), 2.76-2.87 (m, 4H), 3.22 (s, 3H), 3.44 (t, 2H), 6.80 (brs, 2H),7.04-7.23 (m, 4H), 7.52 (d, 1H), 7.61 (brs, 1H), 7.70 (s, 1H), 10.89 (s,1H).

b) 1-(2-Bromophenyl)-4-(2-methoxyethyl)piperazine

The title compound was prepared in a similar manner to Example 110 (a)but using 1-(2-methoxyethyl)piperazine.

MS (ES) 299 (M+H)⁺.

¹H NMR (CDCl₃) 2.62-2.75 (m, 6H), 3.05-3.15 (m, 4H), 3.38 (s, 3H), 3.55(t, 2H), 6.91 (td, 1H), 7.06 (dd, 1H), 7.22-7.30 (m, 1H), 7.55 (dd, 1H).

Example 1632-[(Aminocarbonyl)amino]-5-{2-[(1S,4S)-2,5-diazabicyclobicyclo[2,2,1]hept-2-yl]phenyl}thiophene-3-carboxamide

a) The title compound was prepared from2-[(aminocarbonyl)amino-5-bromothiophene-3-carboxamide and tert-butyl5-(2-bromophenyl)-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane]-2-carboxylatein a similar manner to Example 9 (e). On work-up the product wassubjected to cation exchange chromatography, eluting with a gradient of0-10% methanol in dichloromethane. Product fractions were evaporated andtriturated with a mixture of methanol and ether, then collected byfiltration. The BOC-protected product was then stirred in 1:10 water:TFA(2 ml) at room temperature for 1 h, evaporated to dryness, redissolvedin dichloromethane and purified by cation exchange chromatography,eluting with 0-12% ammonia solution (7M in methanol) in dichloromethane.

MS (ES) 358 (M+H)⁺.

¹H NMR (DMSO-D6) 1.62 (d, 1H), 1.85 (d, 1H), 2.75 (d, 1H), 2.85 (d, 1H),3.05 (d, 1H), 3.19 (d, 1H), 3.20 (s, 1H), 3.65 (s, 1H), 4.07 (s, 1H),6.77-6.95 (m, 3H), 6.97 (d, 1H), 7.10-7.33 (m, 4H), 7.63 (brs, 1H),11.00 (s, 1H).

b) tert-Butyl5-(2-bromophenyl)-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane]-2-carboxylate

The title compound was prepared from 1,2-dibromobenzene and tert-butyl(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in a similarmanner to Example 110 (a).

MS (ES) 353 (M+H)⁺.

¹H NMR (DMSO-D6) 1.46 (s, 9H), 1.82-2.00 (m, 2H), 3.27-3.47 (m, 2H),3.57-3.89 (m, 2H), 4.33-4.64 (m, 2H), 6.73 (t, 1H), 7.83 (d, 1H),7.14-7.22 (m, 1H), 7.47-7.56 (m, 1H).

Pharmacological Evaluation of Compounds

IKK-2 Filter Kinase Assay

Compounds were tested for inhibition of IKK-2 using a filter kinaseassay. The test compounds were dissolved to 10 mM in dimethylsulphoxide(DMSO). The compounds) were then diluted 1 in 40 in kinase buffer (50 mMTris, pH 7.4 containing 0.1 mM EGTA, 0.1 mM sodium orthovanadate and0.1% β-mercaptoethanol). 1 in 3 serial dilutions were made from thissolution with 2.5% DMSO in kinase buffer. 20 μl of compound dilution wasadded to wells of a 96 well plate in duplicate. 20 μl 2.5% DMSO inkinase buffer instead of compound was added to control wells (0%inhibition). 20 μl 0.5 M EDTA was added instead of compound tobackground wells (100% inhibition).

10 μl of a mixture of magnesium acetate, unlabelled ATP, and³³P-labelled ATP was added to each well made such that the finalconcentration was 10 mM magnesium acetate, 1 μM ATP and 0.1 μCi ³³P ATP.20 μl of a mixture of IKK-2 (0.15 μg/well), 1-53 GST-IκB (0.5 μg/well)and bovine serum albumin (BSA) (8.5 μg/well) was added to each well tostart the reaction. The final reaction volume was 50 μl.

The kinase reactions were incubated at 21° C. for 80 minutes and thereaction stopped by precipitating the protein by the addition of anequal volume (50 μl) of 20% trichloroacetic acid (TCA). The precipitatewas allowed to form for 10 minutes and then filtered onto a GF/Cunifilter 96 well plate. Each filter was washed twice with approximately1 ml 2% TCA. The filter plate was dried at 30-40° C. for 60 minutes, 20μl scintillant was added to each well and the plate sealed andradioactivity counted on a Packard Topcount microplate scintillationcounter.

When tested in the above assay, the compounds of Examples 1 to 163 gaveIC₅₀ values of less than 10 μM indicating that they are expected to showuseful therapeutic activity.

IKK-1 Filter Kinase Assay

The selectivity of compounds was assessed by testing them for inhibitionof IKK-1 using a filter kinase assay. The assay conditions wereidentical to the IKK-2 filter kinase assay except that a mixture ofIKK-1 (0.25 μg/well) and 1-53 GST IκB (9 μg/well) was added to each wellto start the reaction.

Inhibition of LPS-Induced TNFα Production by PBMCs

The effect of test compounds on nuclear factor kappa B (NFκB) activationin cells was assessed by measuring inhibition of tumour necrosis factoralpha (TNFα) production by human peripheral blood mononuclear cells(PBMCs) stimulated by bacterial lipopolysacchamide (LPS).

Human blood (250 ml), anticoagulated with heparin, was collected fromhealthy volunteers. Aliquots of blood (25 ml) were layered on 20 mlLymphoprep (Nycomed) in 50 ml polypropylene centrifuge tubes. The tubeswere centrifuged (Sorval RT600B) at 2,500 rpm for 30 minutes. The cloudylayer containing PBMCs was collected with a fine tipped Pasteur pipette,transferred into 8 clean polypropylene centrifuge tubes (approximately10 ml per tube) and diluted to 50 ml with phosphate-buffered saline(PBS). These tubes were centrifuged at 2,000 rpm for 8 minutes. PBS (10ml) was added to each cell pellet and the cells were gentlyre-suspended. The cells were pooled in 4 centrifuge tubes, PBS was addedto each tube to make the volume up to 50 ml and the tubes werecentrifuged at 1,400 rpm for 8 minutes. The cell pellets were againre-suspended in 10 ml PBS, pooled in 2 centrifuge tubes, the volume madeup to 50 ml with PBS and the tubes centrifuged at 900 rpm for 10minutes.

The final cell pellets were gently re-suspended in 10 ml tissue culturemedium (RPMI containing 1% heat-inactivated human serum, L-glutamine andpenicillin and streptomycin), combined into 1 tube and the volume madeup to 30 ml with RPMI medium. The cells were counted and the cellsuspension was diluted to 2.6×10⁶ cells/ml.

Test compounds were dissolved in DMSO to 10 mM and diluted 1 in 250 (40μM) with RPMI medium. The compounds were then serially diluted 1 in 3with 0.4% DMSO in RPMI medium. Aliquots of test compound dilutions (50μl) were transferred to the wells of a 96-well plate. Control wellscontained 0.4% DMSO in RPMI instead of compound.

Aliquots of the cell suspension (100 μl) were added to each well and theplates incubated at 37° C. for 30 minutes. 50 μl of 40 μg/ml LPS (Sigma,L-4130) was added to wells to stimulate TNFα production by the cells andthe plates were incubated overnight at 37° C. RPMI medium (50 μl) wasadded to negative control wells instead of LPS. The final incubationvolume was 200 μl.

Plates were centrifuged for 4 minutes at 1,200 rpm and supernatants wereremoved for measurement of TNFα concentration. Viability of theremaining cell pellet was measured using WST-1 reagent (BoehringerMannheim, 1044807). 100 μl RPMI medium containing 10 μl WST-1 reagentwas added to each well and the plates were incubated for 0.5 to 3 h. Theabsorbance at 450 nm was then measured using a 96-well platespectrophotometer.

TNFα in the supernatants (freshly harvested or stored frozen at −20° C.)were measured using an enzyme-linked immnunosorbant assay (ELISA). TheELISA plate was prepared by coating the wells of a 96 well plate with asheep anti-human TNFα monoclonal antibody (100 μl of 1 μg/ml antibodydiluted in coating buffer; 0.5 M carbonate/bicarbonate buffer, pH 9.6containing 0.2 g/l sodium azide) and incubating overnight at 4° C. Blankwells were not coated. The wells were washed once with 0.1% BSA in PBScontaining 0.05% Tween (PBS/Tween) then incubated for 1 h at roomtemperature with 1% BSA in coating buffer (200 μl). The wells were thenwashed 3 times with 0.1% BSA in PBS/Tween.

The samples of supernatant from the PBMC incubation were diluted 1 in 3with 1% BSA in PBS/Tween. 100 μl aliquots of these dilutions were addedto the ELISA plate. Other wells contained 100 μl TNFα standard (10, 3.3,1.1, 0.37, 0.12, 0.04, 0.014 and 0 ng/ml). The ELISA plate was incubatedat room temperature for 2 h before the wells were washed 3 times with0.1% BSA in PBS/Tween. A rabbit anti-human TNFa antibody (100 μl of a2.5 μg/ml solution) was added to each well and the plate incubated atroom temperature for 1.5 h. The wells were then washed 3 times with 0.1%BSA in PBS/Tween. Goat anti-rabbit IgG-horse radish peroxidase conjugate(ICN, 674371; 100 μl of a 1 in 10,000 dilution) was added to each welland the plate incubated at room temperature for 1.5 h. The wells werewashed 3 times with 0.1% BSA in PBS/Tween.

Peroxidase substrate was prepared by dissolving a 1 mg TMB tablet(Sigma, T-5525) in 100 μl DMSO (100 μl) and adding this and 36 μl UBPO(BDH, 30559; 1 g tablet dissolved in 25 ml distilled water) to 10 ml 0.1M citrate/aceate buffer, pH6. 100 μl substrate was added to each welland the plate incubated in the dark at room temperature forapproximately 30 minutes. The reaction was stopped by adding 25 μl 2 Msulphuric acid to each well. The absorbance at 450 nm was measured in a96 well plater spectrophotometer.

1. A compound which is2-[(Aminocarbonyl)amino]-5-[2-(pyrrolidin-3-yloxy)phenyl]-3-thiophenecarboxamide;or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound which is2-[(Aminocarbonyl)amino]-5-[2-(pyrrolidin-3-yloxy)phenyl]-3-thiophenecarboxamide,or a pharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable adjuvant, diluent or carrier.